Novel benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics

ABSTRACT

Benzenesulfonamide compounds having a structure of formula (I) are described. Also described, are methods for synthesizing the compounds and to the use thereof in pharmaceutical compositions for human or veterinary medicine and in cosmetic compositions.

PRIOR APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.14/626,302, filed Feb. 19, 2015, now allowed, which is a Divisional ofU.S. patent application Ser. No. 14/103,470, filed Dec. 11, 2013, nowU.S. Pat. No. 8,980,897, which is a Continuation of U.S. patentapplication Ser. No. 13/774,023, filed Feb. 22, 2013, now U.S. Pat. No.8,633,196, which is a Continuation of U.S. patent application Ser. No.13/381,234, filed Aug. 27, 2012, now U.S. Pat. No. 8,420,632 B2, whichis the United States national phase of PCT/FR2010/051331, filed Jun. 28,2010, which claims foreign priority under 35 U.S.C. §119 of FR 09/54460,filed Jun. 30, 2009, each hereby expressly incorporated by reference inits entirety.

TECHNICAL FIELD

The present invention relates to novel benzenesulfonamide compoundscorresponding to general formula (I) below:

and also to the process for synthesizing same and to the use thereof inpharmaceutical compositions intended for use in human or veterinarymedicine.

The compounds of the present invention act as inhibitors ofTNFα—converting enzyme, also known as TACE. They are consequently of usein the treatment of diseases for which reducing TNFα production is ofgreat interest.

The present invention also relates to the use of the compoundscorresponding to general formula (I) in cosmetic compositions.

PRIOR ART

Adamalysins (“ADAM” or A Disintegrin and Metalloproteinase) are asubfamily of zinc metalloendopeptidase enzymes. Their ectodomaincomprises a protease domain, the activation of which is zinc-dependent,a disintegrin domain and a cysteine-rich domain. To date, at least 30different ADAMs have been identified, of which the first characterizedwas ADAM17, also known as TACE (TNFα-converting enzyme) [Gueydan C etal. Med. Sci 1997, 13, 83-88; Black R. A et al. Nature 1997,385:729-733; Moss et al. Nature 1997, 385:733-736]. The TACE mRNA ispresent in many tissues and more particularly in monocytes, macrophagesand T lymphocytes, but also in keratinocytes for example. TACE isresponsible for the cleavage of pro-TNFα, a 26 kDa membrane protein, soas to result in the release of biologically active soluble TNFα, a 17kDaprotein [Schlondorff et al. Biochem. . 2000, 347, 131-138]. The solubleTNFα released by the cell is capable of acting on sites very remote fromthe site of synthesis.

TNFα is involved in a large number of pro-inflammatory biologicalprocesses [Aggarwal et al, Eur. Cytokine Netw., 1996, 7: 93-124].Several pharmacological and clinical studies have shown in an obviousmanner that blocking the effects of TNFα with specific anti-TNFαantibodies or anti-TNFα biologicals (Etanercept, Adalimumab, Infliximab)is beneficial in the treatment of autoimmune diseases such as rheumatoidarthritis [Feldman et al. Lancet, 1994, 344, 1105],non-insulin-dependent diabetes mellitus [Lohmander L.S et al. ArthritisRheum, 1993, 36, 1214-1222], or Crohn's disease [MacDonald et al. Clin.Exp. Immunol. 1990, 81, 301].

TNFα also plays a fundamental role during the inflammantory phenomenontriggered in psoriasis lesions. Serum TNFα levels are elevated inpsoriatic patients [Mussi A et al. J. Biol. Regul. Homeost Agents, 1997,11, 115-118]; TNFα levels are also elevated in the actual psoriasisplaques [Bonifati C. et al. Clin. Exp. Dermatol., 1994, 19, 383-387].The key cells in the physiopathology of psoriasis are keratinocytes,dendritic cells and certain T lymphocytes. The interaction between thesefamilies of cells results in an inflammatory cascade that leads to thecharacteristic psoriasis lesions with release of TNFα [Kupper TS, N.Engl. J. Med, 2003, 349, 1987-1990]. Clinical studies for the treatmentof moderate to severe plaque psoriasis with anti-TNFα biologicals(Etanercept, Adalimumab, Infliximab) have demonstrated their efficacyboth on psoriasis lesions and on the quality of life of the patients[Ortonne JP, Annales de dermatologie et de venereologie {Annals ofdermatology and venereology], 2005, 132 (8-9 pt2), 4S6-9 and 2005, 132,9S01-9S70]. Thus, compounds which inhibit TNFα production are of greatinterest for the treatment of inflammatory diseases and diseasesinvolving TNFα release.

SUMMARY OF THE INVENTION

Our invention therefore describes novel molecules which inhibit the TACEenzyme (TNFα-converting enzyme) and, as a result, inhibit the secretionof soluble TNFα (active form of TNFα) by cells. These novel moleculesare therefore potential active ingredients for the treatment ofpathological conditions which involves a decrease or an inhibition ofTNFα production.

By way of illustration, and in a nonlimiting manner, these pathologicalconditions are, for example, septic shock, hemodynamic shock, malaria,inflammatory bowel diseaases (IBDs) such as Crohn's disease andulcerative colitis, inflammatory bone diseases, mycobacterialinfections, meningitis, fibrotic diseases, cardiac diseases, ischemicattack, transplant rejection, cancer, atherosclerosis, obesity, diseasesinvolving angiogenesis phenomena, autoimmune diseases, osteoarthritis,rheumatoid arthritis, ankylosing spondylitis, juvenile chronicarthritis, multiple sclerosis, HIV, non-insulin-dependent diabetesmellitus, allergic diseases, asthma, chronic obstructive pulmonarydisease (COPD), occular inflammation, inflammatory skin diseases,psoriasis, atopic dermatitis and psoriatic arthritis.

These molecules are also potential active ingredients for the treatmentof neurological pathological conditions that are inflammatory in nature,for which reducing TNFα production would be of great interest. Thesepathological conditions listed hereinafter in a nonlimiting manner are,for example, Alzheimer's disease, Parkinson's disease, parkinsoniandisorders, amyotrophic lateral sclerosis, autoimmune diseases of thenervous system, autonomic diseases of the nervous system, dorsal pain,cerebral edema, cerebrovascular disorders, dementia, nervous systemnerve fiber demyelinating autoimmune diseases, diabetic neuropathies,encephalitis, encephalomyelitis, epilepsy, chronic fatigue syndrome,giant cell arteritis, Guillain-Barré syndrome, headaches, multiplesclerosis, neuralgia, peripheral nervous system diseases,polyneuropathies, polyradiculoneuropathy, radiculopathy, respiratoryparalysis, spinal cord diseases, Tourette's syndrome, central nervoussystem vasculitis, Huntington's disease and stroke. A large variety ofTACE inhibitors is already known as indicated below. However, a largenumber of these inhibitors do not act selectively on the TACE enzymecompared with other enzymes of the family of ADAMs and/or of matrixmetalloproteinases (MMPs). As it happens, the nonselective inhibition ofthese enzyme families induces adverse side effects observed in vivo. Forexample, the inhibition of MMP-1 (collagenase-1) has been associatedwith musculoskeletal toxicity problems.

As a nonselective inhibitor, mention may also be made of Apratastat, aknown inhibitor tested clinically in phase 2 for the treatment ofrheumatoid arthritis (Curr Opin Investig Drugs. 2006 Nov;7(11),1014-1019). This inhibitor is not selective for the TACE enzymecompared with certain MMPs (WO 00/44709; page 251, table 10, example61). Other TACE inhibitors which are also known and are part of the samefamily as Apratastat, namely that of cyclic benzenesulfonamidederivatives, have been described in WO 00/44709 and WO 97/18194. Otherpatents (WO 96/00214, WO 97/22587) claim MMP and/or TACE inhibitors forwhich the benzenesulfonamide part is separated from the hydroxamic acidfunction by a single carbon atom. Publications describing MMP inhibitorsof this type more broadly are also the publication by MacPherson et al.J. Med. Chem. 1997, 40, 2525 and the publication by Tamura et al. J.Med. Chem. 1998, 41, 640. Other examples of MMP/TACE inhibitors forwhich the sulfonamide function is separated from the hydroxamic acid bya series of two carbon atoms forming a ring are described in patents WO98/16503, WO 98/16506, WO 98/16514 and WO 98/16520. Other examples ofMMP inhibitors for which the sulfonamide function is separated from thehydroxamic acid by a series of two carbon atoms are also described in WO2008/045671. As it happens, the applicant has now discovered,unexpectedly and surprisingly, that novel compounds of general formula(I) exhibit a very good TACE-inhibiting activity, and in particularinhibit the TACE enzyme selectively compared with other ADAMs and MMPs.Thus, the present invention relates to compounds of general formula (I)below:

in which:

R₁ represents a hydrogen, an alkyl radical, a substituted alkyl radical,an alkenyl radical, a substituted alkenyl radical, an alkynyl radical, asubstituted alkynyl radical, an aralkyl radical, a substituted aralkylradical, a heteroaralkyl radical, a substituted heteroaralkyl radical, a—C(O)—R₄ radical, an —SO₂—R₄ radical, or a C(O)OR₄ radical, R₄ havingthe meanings given hereinafter;

R₂ is a hydrogen atom or a lower alkyl radical;

R₃ is an alkyl radical, a substituted alkyl radical, an alkenyl radical,a substituted alkenyl radical, an alkynyl radical, a substituted alkynylradical, an aryl radical, a substituted aryl radical, an aralkylradical, a substituted aralkyl radical, a heterocyclic radical, asubstituted heterocyclic radical, a cycloalkyl radical, a substitutedcycloalkyl radical, a heteroaryl radical, a substituted heteroarylradical, a heteroaralkyl radical or a substituted heteroaralkyl radical;

R₄ is an alkyl radical, a substituted alkyl radical, an alkenyl radical,a substituted alkenyl radical, an alkynyl radical, a substituted alkynylradical, an aryl radical, a substituted aryl radical, an aralkyl radicalor a substituted aralkyl radical;

n can take the values of 0, 1, 2 or 3;

and also the addition salts of the compounds of general formula (I) witha pharmaceutically acceptable acid, the addition salts of the compoundsof general formula (I) with a pharmaceutically acceptable base, and theenantiomers of the compounds of general formula (I).

Among the addition salts of the compounds of general formula (I) with apharmaceutically acceptable acid, mention may preferably be made of thesalts with an organic acid or with an inorganic acid.

The suitable inorganic acids are, for exaple, hydrohalic acids such ashydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid andphosphoric acid.

The suitable organic acids are, for example, acetic acid,trifluoroacetic acid, trichloroacetic acid, propionic acid, glycolicacid, pyruvic acid, succinic acid, benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, para-toluenesulfonic acid, salicylic acid,picric acid, citric acid, oxalic acid, tartaric acid, malonic acid,maleic acid, camphorsulfonic acid and fumaric acid.

Among the addition salts of the compounds of general formula (I) with apharmaceutically acceptable base, mention may preferably be made of thesalts with an organic base or with an inorganic base.

The inorganic bases are, for example, potassium hydroxide, sodiumhydroxide, lithium hydroxide or calcium hydroxide.

The suitable organic bases comprise amines and amino acids. Among theamines, mention may, for example, be made of aliphatic or aromatic,primary, secondary or tertiary amines, such as methylamine, ethylamine,ethanolamine, propylamine, isopropylamine, the 4 isomers of butylamine,dimethylamine, diethylamine, diethanolamine, dipropylamine,diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine,diethanolphenylamine, trimethylamine, triethylamine, tripropylamine,quinuclidine, pyridine, quinoline or isoquinoline.

Among the amino acids, mention may, for example, be made of lysine,arginine and ornithine.

According to the present invention, the term “lower alkyl radical”denotes a linear or branched, saturated hydrocarbon-based chaincontaining from 1 to 4 carbon atoms.

According to the present invention, the term “alkyl radical” denotes alinear or branched, saturated hydrocarbon-based chain containing from 1to 10 carbon atoms.

According to the present invention, the term “alkenyl radical” denotes alinear or branched, unsaturated hydrocarbon-based chain containing from2 to 10 carbon atoms and comprising one or more double bonds.

According to the present invention, the term “alkynyl radical” denotes alinear or branched, unsaturated hydrocarbon-based chain containing from2 to 10 carbon atoms and comprising one or more triple bonds.

According to the present invention, the term “substituted alkyl radical”denotes a linear or branched, saturated hydrocarbon-based chaincontaining from 1 to 10 carbon atoms and substituted with one or moreradicals chosen from a halogen atom, an alkoxy radical and a hydroxylradical.

According to the present invention, the term “substituted alkenylradical” denotes a linear or branched, unsaturated hydrocarbon-basedchain containing from 2 to 10 carbon atoms, comprising one or moredouble bonds and substituted with one or more radicals chosen from ahalogen atom, an alkoxy radical and a hydroxyl radical.

According to the present invention, the term “substituted alkynylradical” denotes a linear or branched, unsaturated hydrocarbon-basedchain containing from 2 to 10 carbon atoms, comprising one or moretriple bonds and substituted with one or more radicals chosen from ahalogen atom, an alkoxy radical and a hydroxyl radical.

According to the present invention, the term “cycloalkyl” denotes acyclic saturated hydrocarbon-based chain containing from 3 to 7 carbonatoms.

According to the present invention, the term “substituted cycloalkyl”denotes a cyclic saturated hydrocarbon-based chain containing from 3 to7 carbon atoms and substituted with one or more radicals chosen from ahalogen atom, an alkoxy radical and a hydroxyl radical.

According to the present invention, the term “aryl radical” denotes anaromatic hydrocarbon-based ring or two fused aromatic hydrocarbon-basedrings.

The preferred aryl radicals are chosen from phenyl and naphthylradicals.

According to the present invention, the term “substituted aryl radical”denotes an aromatic hydrocarbon-based ring or two fused aromatichydrocarbon-based rings which is (are) substituted with one or moregroups of atoms chosen from an alkyl, an alkoxy, an aryl, a halogen, ahydroxyl, a cyano, a trifluoromethyl and a nitro.

According to the present invention, the term “aralkyl radical” denotesan alkyl substituted with an aryl.

According to the present invention, the term “substituted aralkylradical” denotes an alkyl substituted with a substituted aryl.

According to the present invention, the term “heterocyclic radical”denotes a saturated or unsaturated, cyclic or polycyclichydrocarbon-based chain comprising one or more heteroatoms chosen fromO, S and N.

According to the present invention, the term “substituted heterocyclicradical” denotes a heterocyclic radical substituted with one or moregroups of atoms chosen from an alkyl, an alkoxy, a halogen, a hydroxyl,a cyano, a trifluoromethyl and a nitro.

According to the present invention, the term “heteroaryl radical”denotes an aromatic heterocyclic radical, i.e. a cyclic or polycyclicaromatic hydrocarbon-based chain, comprising one or more heteroatomschosen from O, S and N.

According to the present invention, the term “substituted heteroarylradical” denotes a heteroaryl radical substituted with one or moregroups of atoms chosen, for example, from an alkyl, an alkoxy, an aryl,a substituted aryl, a halogen, a hydroxyl, a cyano, a trifluoromethyland a nitro.

According to the present invention, the term “heteroaralkyl radical”denotes an alkyl radical substituted with a heteroaryl radical.

According to the present invention, the term “substituted heteroaralkylradical” denotes a heteroaralkyl radical substituted with one or moregroups of atoms chosen from an alkyl, an alkoxy, a halogen, a hydroxyl,a cyano, a trifluoromethyl and a nitro.

According to the present invention, the term “alkoxy radical” denotes anoxygen atom substituted with an alkyl radical.

According to the present invention, the term “halogen atom” denotes afluorine, chlorine, bromine or iodine atom.

Among the compounds of general formula (I) which fall within the contextof the present invention, mention may in particular be made of thefollowing compounds:

1)3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide

2)(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide

3)(S)-3-(4-benzyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide

4)(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide

5)(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

6)(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmethoxy)benzenesulfonylamino]propionamide

7)(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)propionamide8)(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide

9)(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide

10) benzyl4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]ethyl)piperazine-1-carboxylate

11)(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy)benzenesulfonylamino]propionamide

12)(R)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

13)(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-piperazin-1-yl-propionamide

14)(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamidehydrochloride

15) tert-butyl3-{4-[(S)-2-hydroxycarbamoyl-2-(4-methanesulfonylpiperazin-1-yl)ethylsulfamoyl]phenoxymethyl}-2-methylindole-1-carboxylatedi(trifluoroacetate)

16)(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

17)(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

18)(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

19)(S)-2-(4-ethylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

20)(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trifluoromethyl-benzyl)piperazin-1-yl]propionamide

21)(S)-N-hydroxy-2-[4-(4-methylbenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

22)(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide

23)(S)-N-hydroxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

24)(S)-N-hydroxy-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

25)(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide

26)(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propionamide

27) (S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide

28)(S)-2-(4-acetylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

29)(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-{propyl-[4-(quinolin-4-ylmethoxy)benzenesulfonyl]amino}propionamide

30)(S)-2-(4-benzenesulfonylpiperazin-1-yl)-N-hydroxy-3-[4-(pyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide

31)(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(1-methylpiperidin-4-ylmethoxy)benzenesulfonylamino]propionamide

32)(S)-2-[4-(4-fluorobenzoyl)piperazin-1-yl]-N-hydroxy-3-[4-(3-m-tolyl-propoxy)benzenesulfonylamino]propionamide

33)(S)-N-hydroxy-3-[4-(2-methylnaphthalen-1-ylmethoxy)benzenesulfonylamino]-2-(4-propionylpiperazin-1-yl)propionamide

34)(S)-N-hydroxy-3-[4-(4-methylpentyloxy)benzenesulfonylamino]-2-(4-phenylacetylpiperazin-1-yl)propionamide

35)(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylpyridin-4-ylmethoxy)benzenesulfonylamino]propionamide

36)(S)-2-(3-acetylimidazolidin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

37)(S)-3-[4-(3,5-dimethylbenzyloxy)benzenesulfonylamino]-N-hydroxy-2-imidazolidin-1-yl-propionamide

38)(S)-N-hydroxy-2-(4-methanesulfonyl-[1,4]diazepan-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

39)(S)-2-(4-benzyl-[1,4]diazepan-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

40)(S)-2-[1,4]diazocan-1-yl-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide.

41)(S)-N-hydroxy-3-[4-(2-methylbenzofuran-3-ylmethoxy)benzenesulfonylamino]-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propionamide

42)(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-isopropyl-1H-indol-3-ylmethoxy)benzenesulfonylamino]propionamide

The compounds of general formula (I) are prepared according to thereaction scheme (Scheme 1) presented below.

According to Scheme 1, the compounds (3) are obtained by reactionbetween the amino acid (1) H-DAP(Boc)-OMe.HCl or H-(D)-DAP(Boc)-OMe.HCland the compound (2) (commercial or prepared beforehand) in the presenceof an organic tertiary base such as diisopropylethylamine ortriethylamine at a temperature of between 60° C. and 120° C. Thecompounds (4) are obtained by deprotection of the amine function ofcompounds (3) according to conventional methods such as, for example,the use of a solution of hydrochloric acid in isopropanol.

A reaction between the compound (4) and 4-hydroxybenzenesulfonylchloride O-protected with a benzyl group for example (P═CH₂—Ph) (5) inthe presence of a tertiary amine such as, for example, triethylamine indichloromethane, produces the compound (6). An N-alkylation of thesulfonamide function can then be carried out by reaction with an alkylhalide in the presence of a base such as, for example, potassiumcarbonate in a solvent such as DMF, so as to give the derivative (7).The compound (8) is obtained by deprotection according to methods knownby those skilled in the art for deprotecting a phenol function. Thecompound (9) is obtained by alkylation of the phenol function of thecompound (8) by reaction with an alkyl halide in the presence of a basesuch as, for example, cesium carbonate in acetone, or via a Mitsunobureaction with a primary alcohol derivative in the presence oftriphenylphosphine and of diisopropyl azodicarboxylate for example. Thecompound (10) is obtained via a saponification reaction in the presenceof a base such as lithium hydroxide in the presence of water and oftetrahydrofuran for example. In a final step, the compound (11) isobtained by coupling between O-(tert-butyldimethylsilyl)hydroxylaminefor example and the derivative (10) under conventional peptide couplingconditions, using, for example,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,hydroxybenzotriazole or TBTU as coupling agents, and triethylamine ordiisopropylethylamine as base, in a solvent such as dichloromethane ordimethylformamide. The deprotection of the silylated hydroxamic acidintermediately formed is carried out in situ or by washing with aslightly acidic aqueous solution, so as to give the compound (11).

Another alternative for obtaining the compound (11) is presented inScheme 2 below.

According to the synthesis scheme of Scheme 2, the derivative (3) canoptionally be alkylated in the presence of a base such as sodium hydrideand of an alkyl halide in dimethylformamide, for example, so as to givethe compound (12), from which the compound (13) is obtained according toconventional methods for deprotecting amines, for instance the use of asolution of hydrochloric acid in isopropanol. The compound (14) isprepared beforehand from the commercially available4-hydroxybenzenesulfonic acid sodium salt by alkylation with an alkylhalide in the presence of a base such as sodium hydroxide, for example,in a mixture of solvents such as isopropanol and water, for example. Thecompound (15) is then obtained by reacting the derivative (14) withoxalyl chloride in the presence of dimethylformamide in dichloromethane,for example. _o The derivative (9) is obtained by reaction between thecompounds (13) and (15) in the presence of a base such as triethylaminein dichloromethane, for example.

An alternative synthesis pathway for obtaining the compound (11) is alsopresented in Scheme 3 below.

According to Scheme 3, the compound (17) is obtained by reaction betweenthe amino acid (1) H-DAP(Boc)-OMe.HCl or H-(D)-DAP(Boc)-OMe.HCl and thecompound (16) (prepared beforehand by reacting bis(2-chloroethyl)aminefor example and benzyl bromide in the presence of potassium carbonate inacetonitrile) in the presence of an organic tertiary base such asdiisopropylethylamine at a temperature of approximately 120° C. Afterdeprotection of the amine function, the compound (18) is condensed withsulfonyl chloride (15) so as to give the derivative (19). AnN-alkylation of the sulfonamide function can then be carried out byreaction with an alkyl halide in the presence of a base such as, forexample, potassium carbonate in a solvent such as DMF, so as to give thederivative (20). The compound (21) is obtained according to theconventional conditions for hydrogenation of the compound (20) in thepresence of palladium-on-carbon in a solvent such as ethanol forexample. The compound (9) is obtained according to the conventionalsynthesis methods, for example, by reaction of the compound (21) with anacyl chloride, or a sulfonyl chloride in the presence of triethylamine,or by reaction with an alkyl halide in the presence of a base such assodium hydride, for example. The compound (10) is obtained via asaponification reaction in the presence of a base such as lithiumhydroxide in the presence of water and of tetrahydrofuran, for example.In a final step, the compound (11) is obtained by coupling betweenO-(tert-butyldimethylsilyl)hydroxylamine, for example, and thederivative (10) under conventional peptide coupling conditions, using,for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride, hydroxybenzotriazole or TBTU as coupling agents, andtriethylamine or diisopropylethylamine as base, in a solvent such asdichloromethane or dimethylformamide. The deprotection of the silylatedhydroxamic acid intermediately formed is carried out in situ or bywashing with an acidic aqueous solution, so as to give the compound(11).

An alternative synthesis pathway for the compounds with R1 representinga —(CO)—R₄ radical is described in Scheme 4.

After deprotection of the amine function of the compound (17) accordingto conventional conditions for hydrogenation in the presence ofpalladium-on-carbon in a solvent such as ethanol for example, thecompound (22) is obtained. The compound (23) is obtained by reactionwith an acyl chloride, R₄COCI, in the presence of a base such astriethylamine. When R₂ represents a lower alkyl radical, an N-alkylationof the carbamate is then carried out by reaction with an alkyl halide inthe presence of a base such as, for example, potassium carbonate in asolvent such as DMF, so as to give the derivative (24). The compound(25) is prepared via a saponification reaction in the presence of a basesuch as lithium hydroxide in the presence of water and oftetrahydrofuran, for example. Coupling between 0-allylhydroxylaminehydrochloride, for example, and the derivative (25) makes it possible toobtain the compound (26) under conventional peptide coupling conditions.For this, use is made, for example, of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,hydroxybenzotriazole or TBTU as coupling agents, and triethylamine ordiisopropylethylamine as base. The reaction is carried out in a solventsuch as dichloromethane or dimethylformamide. After deprotection of theamine function of the compound (26) according to conventional methods,the compound (27) is obtained. It is condensed with sulfonyl chloride(15) so as to give the compound (28). In a final step, the compound (29)is obtained by deprotection of the hydroxylamine function of thecompound (28) according to conventional methods such as, for example,treatment with tetrakis(triphenylphosphine)palladium(O) and potassiumcarbonate in methanol. According to the present invention, the preferredcompounds of general formula (I) are those for which:

R₁ represents a hydrogen, an alkyl radical, a substituted alkyl radical,an alkenyl radical, a substituted alkenyl radical, an alkynyl radical, asubstituted alkynyl radical, an aralkyl radical, a substituted aralkylradical, a heteroaralkyl radical, a substituted heteroaralkyl radical, a—C(O)—R₄ radical, an —SO₂—R₄ radical or a C(O)OR₄ radical, R₄ having themeanings given hereinafter;

R₂ is a hydrogen atom or a a lower alkyl radical;

R₃ is an aryl radical, a substituted aryl radical, an aralkyl radical, asubstituted aralkyl radical, a heterocyclic radical, a substitutedheterocyclic radical, a heteroaryl radical, a substituted heteroarylradical, a heteroaralkyl radical or a substituted heteroaralkyl radical;

R₄ is an alkyl radical, a substituted alkyl radical, an alkenyl radical,a substituted alkenyl radical, an alkynyl radical, a substituted alkynylradical, an aryl radical, a substituted aryl radical, an aralkyl radicalor a substituted aralkyl radical;

n can take the values of 0, 1 or 2;

and also their addition salts with a pharmaceutically acceptable acid,their addition salts with a pharmaceutically acceptable base, and theenantiomers of said compounds.

According to the present invention, the particularly preferred compoundsof general formula (I) are those for which:

R₁ represents a hydrogen, an alkyl radical, a substituted alkyl radical,an alkenyl radical, a substituted alkenyl radical, an alkynyl radical, asubstituted alkynyl radical, an aralkyl radical, a substituted aralkylradical, a —C(O)—R₄ radical or an —SO₂—R₄ radical, R₄ having themeanings given hereinafter;

R₂ is a hydrogen atom or a lower alkyl radical;

R₃ is an aryl radical, a substituted aryl radical, an aralkyl radical, asubstituted aralkyl radical, a heterocyclic radical, a substitutedheterocyclic radical, a heteroaryl radical, a substituted heteroarylradical, a heteroaralkyl radical or a substituted heteroaralkyl radical;

R₄ is an alkyl radical, a substituted alkyl radical, an aryl radical, asubstituted aryl radical, an aralkyl radical or a substituted aralkylradical;

n can take the values of 1 or 2;

and also their addition salts with a pharmaceutically acceptable acid,their addition salts with a pharmaceutically acceptable base, and theenantiomers of said compounds.

According to the present invention, the more particularly preferredcompounds of general formula (I) are those for which:

R₁ represents an alkyl radical, a substituted alkyl radical, an aralkylradical, a substituted aralkyl radical, a —C(O)—R₄ radical or an —SO₂—R₄radical, R₄ having the meanings given hereinafter;

R₂ is a hydrogen atom;

R₃ is an aryl radical, a substituted aryl radical, an aralkyl radical, asubstituted aralkyl radical, a heterocyclic radical, a substitutedheterocyclic radical, a heteroaryl radical, a substituted heteroarylradical, a heteroaralkyl radical or a substituted heteroaralkyl radical;

R₄ is an alkyl radical, a substituted alkyl radical, an aryl radical, asubstituted aryl radical, an aralkyl radical or a substituted aralkylradical;

n takes the value of 1;

and also their addition salts with a pharmaceutically acceptable acid,their addition salts with a pharmaceutically acceptable base, and theenantiomers of said compounds.

According to the present invention, the even more particularly preferredcompounds of general formula (I) are those for which:

R₁ represents an alkyl radical, a substituted alkyl radical, an aralkylradical, a substituted aralkyl radical, a —C(O)—R₄ radical or an —SO₂—R₄radical, R₄ having the meanings given hereinafter;

R₂ is a hydrogen atom;

R₃ is a heterocyclic radical, a substituted heterocyclic radical, aheteroaryl radical, a substituted heteroaryl radical, a heteroaralkylradical or a substituted heteroaralkyl radical;

R₄ is an alkyl radical, a substituted alkyl radical, an aryl radical, asubstituted aryl radical, an aralkyl radical or a substituted aralkylradical;

n takes the value of 1;

and also their addition salts with a pharmaceutically acceptable acid,their addition salts with a pharmaceutically acceptable base, and theenantiomers of said compounds.

According to the present invention, the most particularly preferredcompounds of general formula (I) are those for which:

R₁ represents an alkyl radical, a substituted alkyl radical, an aralkylradical, a substituted aralkyl radical, a —C(O)—R₄ radical or an —SO₂—R₄radical, R₄ having the meanings given hereinafter;

R₂ is a hydrogen atom;

R₃ is a heteroaryl radical or a substituted heteroaryl radical;

R₄ is an alkyl radical, a substituted alkyl radical, an aryl radical, asubstituted aryl radical, an aralkyl radical or a substituted aralkylradical;

n takes the value of 1;

and also their addition salts with a pharmaceutically acceptable acid,their addition salts with a pharmaceutically acceptable base, and theenantiomers of said compounds.

The compounds according to the invention exhibit a very goodTACE-inhibiting activity and, in particular, they inhibit the TACEenzyme selectively compared with other ADAMs and MMPs. This TACEenzyme-inhibiting activity is measured in an enzymatic assay andquantified via the measurement of an IC₅₀ (inhibitory concentrationnecessary to obtain 50% inhibition of the TACE enzyme), as described inexample 28. The compounds of the present invention have an IC₅₀ for TACEless than or equal to 10 μM and more particularly less than or equal to1 μM. Advantageously, the compounds of the present invention have anIC₅₀ for TACE less than or equal to 0.5 μM.

Advantageously, these compounds are also very selective for TACEcompared with the other ADAMs and MMPs (assay described in example 29):ther inhibitory activity is at least 10 times greater for TACE than forother ADAMs and MMPs (i.e. the IC₅₀ value for TACE is at least 10 timessmaller than that for other ADAMs and MMPs), and more advantageously atleast 100 times greater.

TACE (TNFα-converting enzyme) catalyses the formation of solubleTNF-alpha from the precursor protein (transmembrane TNFα) bound to themembranes of certain cells. TNFα is a pro-inflammatory cytokine which isknown to play a role in many pathological conditions with aninflammatory nature.

The invention is therefore directed toward the use of at least onecompound of general formula (I) as defined above, for the treatment ofpathological conditions and disorders linked to TNFα release. A TACEenzyme inhibitor of general formula (I) decreases TNFα production. As aresult, it is of use for the treatment of pathological conditions linkedto TNFα release.

The invention is also directed toward the use of at least one compoundof general formula (I) as defined above, for preparing a pharmaceuticalor cosmetic composition in which said compound has TACEenzyme-inhibiting activity.

It is therefore directed toward the use of at least one compound ofgeneral formula (I) as defined above, for the treatment of pathologicalconditions or disorders which are improved by inhibiting the TACEenzyme.

The invention also relates to a method of therapeutic (human or animal)or cosmetic treatment, which consists of the administration or theapplication of a pharmaceutical or cosmetic composition comprising acompound of general formula (I) as a TACE inhibitor and, consequently,as an inhibitor of soluble TNFα production.

Thus, the invention relates to the use of at least one compound ofgeneral formula (I) as defined above, for the treatment of pathologicalconditions or disorders linked to TNFα production.

The invention also relates to the use of a compound of general formula(I) as defined above, for preparing a medicament intended for thetreatment of pathological conditions for which reducing TNFα productionwould be of great interest.

Indeed, the compounds used according to the invention are particularlysuitable for the treatment and prevention of disorders/diseaes such asthe inflammatory diseases listed hereinafter, but are not limitedthereto, such as septic shock, hemodynamic shock, malaria, inflammatorybowel diseases (IBDs) such as Crohn's disease and ulcerative colitis,inflammatory bone diseases, mycobacterial infections, meningitis,fibrotic diseases, cardiac diseases, atherosclerosis, obesity, ischemicattack, transplant rejection, cancer, diseases involving angiogenesisphenomena, autoimmune diseases, osteoarthritis, rheumatoid arthritis,ankylosing spondylitis, juvenile chronic arthritis, multiple sclerosis,HIV, non-insulin-dependent diabetes mellitus, allergic diseases, asthma,chronic obstructive pulmonary disease (COPD), inflammatory skindiseases, psoriasis, atopic dermatitis and psoriatic arthritis.

These molecules are also potential active ingredients for the treatmentof neurological pathological conditions with an inflammatory nature, forwhich reducing TNFα production would be of great interest. Thesepathological conditions listed hereinafter in a nonlimiting manner are,for example, Alzheimer's disease, Parkinson's disease, parkinsoniandisorders, amyotrophic lateral sclerosis, autoimmune diseases of thenervous system, autonomic diseases of the nervous system, dorsal pain,cerebral edema, cerebrovascular disorders, dementia, nervous systemnerve fiber demyelinating autoimmune diseases, diabetic neuropathies,encephalitis, encephalomyelitis, epilepsy, chronic fatigue syndrome,giant cell arteritis, Guillain-Barré syndrome, headaches, multiplesclerosis, neuralgia, peripheral nervous system diseases,polyneuropathies, polyradiculoneuropathy, radiculopathy, respiratoryparalysis, spinal cord diseases, Tourette's syndrome, central nervoussystem vasculitis, Huntington's disease and stroke.

The invention relates to the use of a compound of general formula (I) asdefined above, for preparing a medicament intended for the treatment ofpathological conditions with an inflammatory nature, in which TNFα isinvolved.

The invention relates to the use of a compound of general formula (I) asdefined above, for preparing a medicament intended for the treatment ofinflammatory skin diseases, of psoriasis, of atopic dermatitis or ofpsoriatic arthritis.

A subject of the present invention is also a pharmaceutical compositionintended in particular for the treatment of the abovementionedconditions, and which is characterized in that it comprises, in acarrier which is pharmaceutically acceptable and compatible with themethod of administration selected for this composition, at least onecompound of general formula (I). This compound of general formula (I)can also be in one of its enantiomeric forms or in the form of one ofits pharmaceutically acceptable salts. Several examples of preparationof active compounds of formula (I) according to the invention, and alsoof the results of biological activity of such compounds, will now begiven by way of illustration and without being in any way limiting innature.

Exemplary Embodiments

The compounds of general formula (I) are characterized by proton NMRanalysis on a Bruker Avance 400MHz instrument.

EXAMPLE 13-[(4-but-2-ynyloxybenzenesulfonyl)methylamimo]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide1-1: Dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate

19.5 g (141 mmol) of potassium carbonate and then 19.5 ml (134 mmol) ofdimethyl bromomalonate are added to a solution of 25 g (134 mmol) oftert-butyl piperazine-1-carboxylate in 300 ml of acetonitrile. Thereaction medium is stirred at ambient temperature for 24 h and thenfiltered in order to remove the insoluble salts, and concentrated undervacuum. The crude residue obtained is purified by chromatography onsilica gel, elution being carried out with a 70/30 heptane/ethyl acetatemixture. 41 g (97%) of dimethyl2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate are obtained in the formof a light oil.

1-2: Dimethyl2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)malonate

3.5 g (87 mmol) of sodium hydride are added portionwise to a solution of25 g (87 mmol) of dimethyl2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate in 250 ml oftetrahydrofuran cooled to 2° C. The reaction medium is stirred atambient temperature for 30 minutes and then brought back to 2° C.,before adding, dropwise, 21 g (87 mmol) of2-bromomethylisoindole-1,3-dione in 200 ml of tetrahydrofuran. Thereaction medium is stirred at ambient temperature for 20 h, treated byadding 500 ml of water and then extracted with ethyl acetate. Theorganic phase is dried over magnesium sulfate, filtered, andconcentrated under vacuum.

The crude product obtained is purified by chromatography on silica gel,elution being carried out with a 70/30 heptane/ethyl acetate mixture.27.5 g (73%) of dimethyl2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(1,3-dioxo-1,3-dihydroisoindo1-2-ylmethyl)malonateare obtained in the form of a white solid.

1-3: Dimethyl2-aminomethyl-2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate A solutionof 2.9 ml (64 mmol) of hydrazine hydrate in 8 ml of methanol is added toa solution of 27.5 g (58 mmol) of dimethyl2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)malonatein 300 ml of methanol cooled beforehand to -5° C. The reaction medium isstirred at from -5° C. to ambient temperature over the course of 3 h.After evaporation and addition of 300 ml of water, the reaction mediumis extracted with ethyl acetate. The organic phases are washed with asaturated aqueous solution of sodium hydrogen carbonate, dried overmagnesium sulfate, filtered and evaporated. The residue obtained ispurified by chromatography on silica gel, elution being carried out withan 8/2 heptane/ethyl acetate mixture and then an increase in polarity upto a 90/10 ethyl acetate/methanol mixture. 10 g (50%) of dimethyl2-aminomethyl-2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate are thusobtained in the form of a light oil.

1-4: Dimethyl2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]malonate

1.1 ml (8 mmol) of triethylamine and then 1.8 ml (7 mmol) of4-but-2-ynyloxybenzenesulfonyl chloride are added to a solution of 2.5 g(7 mmol) of dimethyl2-aminomethyl-2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate in 30 mlof dichloromethane. The reaction medium is stirred at ambienttemperature for 2 hours and then concentrated under vacuum. The crudeproduct obtained is purified by chromatography on silica gel, elutionbeing carried out with a 70/30 heptane/ethyl acetate mixture. 2.1 g(51%) of dimethyl2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]malonateare obtained in the form of a white solid.

1-5: Dimethyl2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-piperazin-1-ylmalonate

2.8 ml of trifluoroacetic acid are added to a solution of 2.1 g (4 mmol)of dimethyl2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]malonatediluted in 30 ml of dichloromethane. After stirring at ambienttemperature for 24 h, a saturated aqueous solution of sodium hydrogencarbonate is added to pH=8 and the reaction medium is extracted withdichloromethane. The organic phases are combined, washed with water,dried over magnesium sulfate, and then filtered and evaporated. 1.7 g(98%) of dimethyl2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-piperazin-1-ylmalonateare obtained in the form of a white solid.

1-6: Dimethyl2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-(4-methanesulfonylpiperazin-1-yl)malonate

0.6 ml (4 mmol) of triethylamine and then 0.3 ml (4 mmol) ofmethanesulfonyl chloride are added to a solution of 1.6 g (4 mmol) ofdimethyl2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-piperazin-1-ylmalonatediluted in 30 ml of dichloromethane. The reaction medium is then stirredat ambient temperature for 3 h and then evaporated to dryness. The cruderesidue is purified by chromatography on silica gel, elution beingcarried out with a 99/1 dichloromethane/methanol mixture. 1.1 g (58%) ofdimethyl2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-(4-methanesulfonylpiperazin-1-yl)malonateare obtained in the form of a white solid.

1-7: Dimethyl2-{(4-but-2-ynyloxybenzenesulfonyl)methylamino]methyl}-2-(4-methanesulfonylpiperazin-1-yl)malonate

120 mg (0.9 mmol) of potassium carbonate and then 56 μl (0.9 mmol) ofmethyl iodide are added to a solution of 400 mg (0.8 mmol) of dimethyl2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-(4-methanesulfonylpiperazin-1-yl)malonatein 10 ml of dimethylformamide. The reaction medium is then stirred atambient temperature for 18 h and then hydrolyzed by adding water andextracted with ethyl acetate. The organic phases are washed with waterand then dried over magnesium sulfate, filtered and concentrated undervacuum. The crude product obtained is purified by chromatography onsilica gel, elution being carried out with a 50/50 heptane/ethyl acetatemixture. 410 mg (100%) of dimethyl2-{[(4-but-2-ynyloxybenzenesulfonyl)methylamino]methyl]-2-(4-methanesulfonylpiperazin-1-yl)malonateare obtained in the form of a white solid.

1-8:3-[(4-But-2-ynyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid /

1.7 ml (1.7 mmol) of an aqueous solution of sodium hydroxide having aconcentration of 1M are added to a solution of 270 mg (0.5 mmol) ofdimethyl2-{[(4-but-2-ynyloxybenzenesulfonyl)methylamino]methyl}-2-(4-methanesulfonylpiperazin-1-yl)malonatein 7 ml of tetrahydrofuran and 2 ml of methanol. The reaction medium isstirred at 40° C. for 15 h and then brought back to pH=6 by adding anaqueous solution of hydrochloric acid having a concentration of 1 M.After evaporation of the solvents under vacuum, the productprecipitates. The residue obtained is taken up in 5 ml of water andstirred for 30 min until precipitation occurs. The product is filteredoff, rinsed with water and then dried under vacuum. 200 mg (87%) of3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid are obtained in the form of a white solid.

1-9:3-[(4-But-2-ynyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide

63 mg (0.5 mmol) of 1-hydroxybenzotriazole and then 88 mg (0.5 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are added toa solution of 200 mg (0.4 mmol) of3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid in 6 ml of dimethylformamide. The reaction medium is stirred for 10min at ambient temperature and then 68 mg (0.5 mmol) ofO-tert-butyldimethysilylhydroxylamine are added. The reaction medium isthen stirred at ambient temperature for 24 h, hydrolyzed by adding 2 mlof a 5% aqueous citric acid solution, and stirred for a further 30minutes. After extraction with ethyl acetate, the organic phase iswashed with water, dried over magnesium sulfate, filtered andconcentrated. The crude residue is purified by chromatography on silicagel, elution being carried out with a 95/5 dichloromethane/methanolmixture. 100 mg (50%) of3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamideare obtained in the form of a white solid with a melting point of 86° C.

¹H NMR (δ, DMSO): 1.91 (s, 3H); 2.63-2.68 (m, 2H); 2.72 (s, 3H);2.72-2.75 (m, 2H); 2.92 (s, 3H); 3.05-3.15 (m, 5H); 3.30-3.38 (m, 2H);4.93 (s, 2H); 7.24 (d, J=6.8 Hz, 2H); 7.79 (d, J=6.8 Hz, 2H); 9.06 (s,1H); 10.77 (s, 1H).

EXAMPLE 2(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide2.1: Sodium salt of 4-but-2-ynyloxybenzenesulfonic acid

50 g (370 mmol) of 1-bromo-2-butyne are added to a solution of 43 g (185mmol) of commercial sodium salt of 4-hydroxybenzenesulfonic acid and of185 ml (185 mmol) of an aqueous solution of sodium hydroxide having aconcentration of 1M, in 800 ml of isopropanol. The reaction medium isheated at 70° C. for 18 h. After evaporation of the isopropanol, theproduct obtained is filtered, rinsed with isopropanol and with diethylether and then dried under vacuum. 46 g (100%) of the sodium salt of4-but-2-ynyloxybenzenesulfonic acid are obtained in the form of a whitesolid.

2.2: 4-But-2-ynyloxybenzenesulfonyl chloride

30 g (107 mmol) of the sodium salt of 4-but-2-ynyloxybenzenesulfonicacid in 120 ml of dimethylformamide are added dropwise to a solution of28 ml (321 mmol) of oxalyl chloride in 120 ml of dichloromethane, cooledbeforehand to -10° C., and then the reaction medium is stirred atambient temperature for 18 h. 800 ml of ice are added and the medium isextracted with ethyl acetate. The organic phases are combined, washedwith water, dried over magnesium sulfate, filtered and concentratedunder vacuum. 22 g (84%) of 4-but-2-ynyloxybenzenesulfonyl chloride areobtained in the form of a beige solid.

2.3: N,N-bis(2-Chloroethyl)methanesulfonamide

8.6 ml (62 mmol) of triethylamine are added to a solution of 5 g (28mmol) of bis(2-chloroethyl)amine hydrochloride in 60 ml ofdichloromethane. The triethylammonium chloride salts precipitate and arefiltered off. 2.4 ml (31 mmol) of methylsulfonyl chloride are then addedto the filtrate obtained, and the reaction medium is stirred at ambienttemperature for 3 h. After the addition of water, the product isextracted with dichloromethane. The organic phase is washed with water,dried over magnesium sulfate, filtered and concentrated. 5.8 g (94%) ofN,N-bis(2-chloroethyl)methanesulfonamide are obtained in the form of abeige solid.

2.4: Methyl(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propanoate

In a Schlenk tube, a solution of 5 g (20 mmol) of methyl(S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and 4.3 g(20 mmol) of N,N-bis(2-chloroethyl)methanesulfonamide in 65 ml ofN,N-diisopropylethylamine is heated at 127° C. with vigorous stirringfor 18 h. After the addition of water, the product is extracted withethyl acetate. The organic phases are combined, washed with water, driedover magnesium sulfate, filtered and concentrated under vacuum. Thecrude product obtained is purified by chromatography on silica gel,elution being carried out with a 50/50 heptane/ethyl acetate mixture.3.3 g (46%) of methyl(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propanoateare obtained in the form of a white solid.

2.5: Methyl (S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoatehydrochloride

15 ml of a solution of hydrochloric acid in isopropanol, having aconcentration of 5-6N are added dropwise to a solution of 2.7 g (7.4mmol) of methyl(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propanoatein 30 ml of methanol. The reaction medium is stirred at 40° C. for 2 h,concentrated under vacuum, and then taken up in 20 ml of methanol and150 ml of diethyl ether. The product precipitates, and is filtered offunder vacuum, rinsed with diethyl ether and then dried under vacuum. 2.3g (100%) of methyl(S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate hydrochlorideare obtained in the form of a white solid.

2.6: Methyl(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate

0.3 ml (2 mmol) of triethylamine and 270 mg (1 mmol) of4-but-2-ynyloxybenzenesulfonyl chloride (prepared as described in 2.2)are added to a solution of 300 mg (1 mmol) of methyl(S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate hydrochloride(prrepared as described in 2.5) in 8 ml of dichloromethane. Afterstirring at ambient temperature for 18 h, water is added and thereaction medium is extracted with dichloromethane. The organic phasesare washed with water, dried over magnesium sulfate, filtered andconcentrated.

The crude product obtained is purified by chromatography on silica gel,elution being carried out with a 50/50 heptane/ethyl acetate mixture.400 mg (85%) of methyl(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoateare obtained in the form of a white solid.

2.7:(S)-3-(4-But-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid

1.3 ml (1.3 mmol) of an aqueous solution of lithium hydroxide having aconcentration of 1M are added to a solution of 400 mg (0.8 mmol) ofmethyl(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoatediluted in 10 ml of tetrahydrofuran cooled beforehand to 0° C. Thereaction medium is stirred at ambient temperature for 20 h. Afterevaporation to dryness, 1.5 ml of an aqueous solution of acetic acidhaving a concentration of 1M are added so as to obtain a pH=6. Theproduct precipitates, and is filtered off, rinsed with water and thenwith diethyl ether and dried under vacuum. 340 mg (89%) of(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid are obtained in the form of a white solid.

2.8:(S)-3-(4-But-2-ynyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide

120 mg (0.9 mmol) of 1-hydroxybenzotriazole and 170 mg (0.9 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are added toa solution of 340 mg (0.7 mmol) of(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid in 8 ml of dimethylformamide. The reaction medium is stirred for 30min, and then 120 mg (0.8 mmol) of 0-tert-butyldimethysilylhydroxylaminein 3 ml of dimethylformamide are added. The reaction medium is thenstirred at ambient temperature for 20 h, and then hydrolyzed with 2 mlof water and 2 ml of a 5% aqueous solution of citric acid. Afterstirring for 30 min, a saturated aqueous solution of sodium hydrogencarbonate is added to pH=8, and then the reaction medium is extractedwith ethyl acetate. The organic phase is dried over magnesium sulfate,filtered and concentrated. The residue is taken up in dichloromethane,filtered, and then dried under vacuum. 80 mg (23%) of(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamideare obtained in the form of a white solid with a melting point of 150°C.

¹H NMR (δ, DMSO): 1.86 (s, 3H); 2.55 (m, 4H); 2.83 (s, 3H); 2.85-2.88(m, 1H); 2.97-3.00 (m, 3H); 3.00-3.06 (m, 2H); 3.10-3.12 (t, J=4.8 Hz,1H); 4.86 (s, 2H); 7.15 (d, J=9.2 Hz, 2H); 7.51 (s, 1H); 7.75 (d, J=9.2Hz, 2H); 8.94 (s, 1H); 10.6 (s, 1H).

EXAMPLE 3(S)-3-(4-benzyloxy-benzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide3.1: N,N-bis-(2-Chloroethyl)methanesulfonamide

14.3 ml (185 mmol) of methanesulfonyl chloride are added slowly to asolution of 15 g (84 mmol) of commercial bis(2-chloroethylamine)hydrochloride and 26 ml (185 mmol) of triethylamine in 200 ml ofdichloromethane and 70 ml of tetrahydrofuran previously stirred for 15min and then filtered in order to remove the triethylammonium chloride.The reaction medium is then stirred at ambient temperature for 18 h,extracted with dichloromethane, and washed with water. The organic phaseis dried over magnesium sulfate, filtered and evaporated. The residueobtained is washed with diisopropyl ether, filtered and then dried undervacuum. 15.3 g (82%) of N,N-bis-(2-chloroethyl)methanesulfonamide areobtained in the form of a solid.

3.2: Methyl(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propanoate

A solution of 9.6 g (44 mmol) ofN,N-bis-(2-chloroethyl)methanesulfonamide and 11.1 g (44 mmol) of methyl2-amino-3-tert-butoxypropanoate hydrochloride in 90 ml ofdiisopropylethylamine is heated at 127° C. for 18 h. The reaction mediumis evaporated to dryness. 31 g of crude residue are obtained andpurified by chromatography on silica gel, elution being carried out witha 9/1 heptane/ethyl acetate mixture and then an increase in polarity upto 4/6. 5.5 g (35%) of methyl(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propanoateare obtained.

3.3: Methyl (S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoatedihydrochloride

A solution of 4 g (11 mmol) of methyl(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propanoate(prepared as described in example 2.4) in 40 ml of methanol and 20 ml ofa solution of hydrochloric acid in isopropanol, having a concentrationof 5 or 6M, is stirred at 40° C. for 18 h and then concentrated undervacuum. The residue obtained is taken up in 200 ml of diethyl ether,filtered, and then dried under vacuum. 3.5 g (94%) of methyl(S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoatedihydrochloride are obtained in the form of a beige solid.

3.4: Sodium salt of 4-benzyloxybenzenesulfonic acid

64 ml (539 mmol) of benzyl bromide are added to a solution of 50 g (215mmol) of the sodium salt of 4-hydroxybenzenesulfonic acid dihydrate in700 ml of isopropanol and 250 ml (250 mmol) of an aqueous solution ofsodium hydroxide having a concentration of 1M. The reaction medium isheated at 70° C. for 20 h. After concentration of the isopropanol undervacuum, the product precipitates and is filtered off. 61 g (100%) of thesodium salt of 4-benzyloxybenzenesulfonic acid are obtained in the formof a white solid.

3.5: 4-Benzyloxybenzenesulfonyl chloride

A solution of 55 ml (639 mmol) of oxalyl chloride in 250 ml ofdichloromethane is added dropwise to a solution of 61 g (213 mmol) ofthe sodium salt of 4-benzyloxybenzenesulfonic acid in 200 ml ofdimethylformamide, while maintaining the temperature between −20° C. and−10° C. After addition, the reaction medium is slowly brought back toambient temperature and then stirred for 18 h, poured onto ice andextracted with ethyl acetate. The organic phase is washed with water andwith a saturated aqueous solution of sodium chloride and concentratedunder vacuum. 54 g (89%) of 4-benzyloxybenzenesulfonyl chloride areobtained in the form of a white solid.

3.6: Methyl(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate

1.1 ml (7.8 mmol) of triethylamine and then 730 mg (2.6 mmol) of4-benzyloxybenzenesulfonyl chloride in 8 ml of dichloromethane are addedto a solution of 800 mg (2.4 mmol) of methyl(S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoatedihydrochloride in 20 ml of dichloromethane and the reaction medium isstirred at ambient temperature for 3 h. After the addition of water, theproduct is extracted with dichloromethane. The organic phase is washedwith water, dried over magnesium sulfate, filtered and concentrated.

The residue obtained is purified by chromatography on silica gel,elution being carried out with an 8/2 heptane/ethyl acetate mixture. 0.9g (75%) of methyl(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoateare obtained in the form of a white solid.

3.7:(S)-3-(4-Benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid

2.6 ml (2.6 mmol) of an aqueous solution of lithium hydroxide having aconcentration of 1M are added to a solution of 900 mg (1.8 mmol) ofmethyl(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoatein 20 ml of tetrahydrofuran and 0.5 ml of water. The reaction medium isstirred at ambient temperature for 18 h and then the THF is evaporatedoff under vacuum. 2.8 ml of an aqueous solution of acetic acid having ofconcentration of 1M and then 30 ml of water are added and the productprecipitates. The suspension is stirred for 30 min at 100° C. and thenbrought back to ambient temperature, filtered and dried under vacuum.750 mg (86%) of(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid are obtained in the form of a white solid.

3.8:(S)-3-(4-Benzyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonyl-piperazin-1-yl)propionamide

224 mg (1.7 mmol) of 1-hydroxybenzotriazole and 318 mg (1.7 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are addedsuccessively to 750 mg (1.5 mmol) of(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid in 20 ml of dimethylformamide. After stirring at ambienttemperature for 20 min, a solution of 244 mg (1.7 mmol) of0-tert-butyldimethylsilylhydroxylamine in 3 ml of dimethylformamide isadded. The reaction medium is then stirred at ambient temperature for 18h and then 2 ml of a saturated aqueous solution of sodium hydrogencarbonate and finally 2 ml of water are added. After extraction withethyl acetate, the organic phase is washed with a saturated aqueoussolution of sodium hydrogen carbonate, dried over magnesium sulfate,filtered and concentrated. The crude residue obtained is taken up in 15ml of ethyl acetate, heated to 70° C. and then brought back to ambienttemperature, filtered and dried under vacuum.

300 mg (34%) of(S)-3-(4-benzyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamideare obtained in the form of a white solid having a melting point of 165°C.

¹H NMR (δ, DMSO): 2.40-2.50 (m, 2H); 2.50-2.60 (m, 2H); 2.84 (s, 3H),3.00-3.05 (m, 4H); 3.06-3.09 (m, 2H); 3.34 (s, 1H); 5.19 (s, 2H); 7.19(d, J=8,4 Hz, 2H); 7.30-7.34 (m, 1H); 7.35-7.47 (m, 5H); 7.73 (d, J=8.4Hz, 2H); 8.93 (s, 1H); 10.65 (s, 1H).

EXAMPLE 4(S)-3-[(4-Benzyloxybenzenesulfonyl)methylamino]N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide

4.1: Methyl(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoate

300 mg (1.9 mmol) of potassium carbonate and then 0.2 ml (3.1 mmol) ofmethyl iodide are added to a solution of 800 mg (1.6 mmol) of methyl(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate(prepared as described in 3.6) in 15 ml of dimethylformamide. Thereaction medium is then stirred at ambient temperature for 20 h,hydrolyzed, and then diluted with ethyl acetate. The product isextracted with ethyl acetate. The organic phases are washed with water,dried over magnesium sulfate and filtered.

The filtrate is concentrated under vacuum, to give 820 mg (100%) ofmethyl(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoatein the form of a white solid.

4.2:(S)-3-[(4-Benzyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid

In a manner analogous to example 3.7, using 820 mg (1,6 mmol) of methyl(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoate,720 mg (90%) of(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid are obtained in the form of a white solid.

4.3:(S)-3-[(4-Benzyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide

In a manner analogous to example 3.8, using 720 mg (1.4 mmol) of(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid, 360 mg (49%) of(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamideare obtained in the form of a white solid with a melting point of 110°C.

¹H NMR (δ, DMSO): 2.58-2.63 (m, 2H); 2.65 (s, 3H); 2.67-2.73 (m, 2H);2.86 (s, 3H); 2.98-3.05 (m, 4H); 3.05-3.09 (m, 1H); 3.24-3.25 (m, 1H);3.28-3.31 (m, 1H); 5.21 (s, 2H); 7.24 (d, J=8.9 Hz, 2H); 7.34-7.44 (m,3H); 7.48 (d, J=7.2 Hz, 2H); 7.72 (d, J=8.9 Hz, 2H); 8.99 (s, 1H); 10.69(s, 1H).

EXAMPLE 5(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide5.1: Methyl(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate

A solution of 2.0 g (3.9 mmol) of methyl(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate(prepared as described in example 3.6) in 60 ml of ethanol, 30 ml ofdioxane and 0.5 ml of glacial acetic acid is degassed under a nitrogenstream and then 200 mg (10% by weight) of palladium-on-carbon at 10% insuspension in 3 ml of dioxane are added. The reaction medium is placedunder a hydrogen atmosphere and stirred at ambient temperature for 18 h.After filtration through celite, the filtrate is hydrolyzed and then theproduct is extracted with ethyl acetate. The organic phase is washedwith water and then with a saturated aqueous solution of sodiumchloride, dried over magnesium sulfate, filtered and concentrated undervacuum. 1.65 g (100%) of methyl(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoateare obtained in the form of a white solid.

5.2: Methyl(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate

280 mg (0.85 mmol) of cesium carbonate followed by 160 mg (0.85 mmol) of4-chloromethyl-2-methylquinoline and by 15 mg of potassium iodide areadded to a solution of 300 mg (0.71 mmol) of methyl(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoatein 10 ml of acetone. The reaction medium is stirred at ambienttemperature for 18 h, filtered and concentrated under vacuum. The crudeproduct is purified by chromatography on silica gel, elution beingcarried out with a 40/60 heptane/ethyl acetate mixture. 130 mg (32%) ofmethyl(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoateare obtained in the form of a white solid.

5.3:(S)-2-(4-Methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid

In a manner analogous to example 3.7, using 130 mg (0.2 mmol) of methyl(S)-2-(4-methanesulfonyl-piperidin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesufonylamino]propanoate,120 mg (99%) of(S)-2-(4-methanesulfonylpiperidin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-propanoicacid are obtained in the form of a white solid.

5.4:(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

In a manner analogous to example 3.8, using 123 mg (0.2 mmol) of(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid, 90 mg (69%) of(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl-amino]propionamideare obtained in the form of a solid with a melting point of 185° C.

¹H NMR (δ, DMSO): 2.54-2.60 (m, 4H); 2.72 (s, 3H); 2.88 (s, 3H),2.88-2.93 (m, 1H); 3.01-3.05 (m, 1H); 3.06-3.12 (m, 4H); 3.13-3.16 (t,J=7 Hz, 1H); 5.76 (s, 2H); 7.38 (d, J=8 Hz, 2H); 7.57 (s, 1H); 7.61-7.66(m, 2H); 7.78-7.85 (m, 3H); 8.02 (d, J=8.2 Hz, 1H); 8.15 (d, J=8.2 Hz,1H); 8.98 (s, 1H); 10.71 (s, 1H).

EXAMPLE 6(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmethoxy)benzenesulfonylamino]propionamide6.1: Methyl(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate

In a manner analogous to example 5.2, using 160 mg (0.9 mmol) of4-chloromethyl-2-methylquinoline and 300 mg (0.7 mmol) of methyl(S)-3-(4-hydroxy-benzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate(prepared as described in 5.1), 130 mg (32%) of methyl(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoateare obtained in the form of a white solid.

6.2:(S)-2-(4-Methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmethoxy)benzenesulfonylamino]propanoicacid

In a manner analogous to example 3.7, using 240 mg (0.6 mmol) of methyl(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmethoxy)benzenesulfonylamino]propanoate,210 mg (91%) of(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmethoxy)benzenesulfonylamino]-propanoicacid are obtained in the form of a white solid.

6.3:(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmethoxy)benzenesulfonylamino]propionamide

In a manner analogous to example 3.8, using 210 mg (0.4 mmol) of(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmethoxy)benzenesulfonylamino]propanoicacid, 70 mg (33%) of(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmethoxy)benzene-sulfonylamino]propionamideare obtained in the form of a beige solid with a melting point of 148°C.

¹H NMR (δ, DMSO): 2.45 (m, 2H); 2.60 (m, 2H); 2.85 (s, 3H); 2.90-3.05(m, 4H); 3.06-3.15 (m, 2H); 3.35 (s, 1H); 5.66 (s, 2H); 7.30 (d, J=8.4Hz, 2H); 7.50-7.60 (m, 4H); 7.70 (d, J=6.2 Hz, 1H); 7.77 (d, J=8.2 Hz,2H); 7.95-8.05 (m, 2H); 8.10 (d, J=6.4 Hz, 1H); 8.94 (s, 1H); 10.70 (s,1H).

EXAMPLE 7(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)propionamide7.1: Methyl(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)propanoate

In a manner analogous to example 5.2, using 0.1 ml (1.3 mmol) of1-bromopropane and 400 mg (0.95 mmol) of methyl(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate(prepared as described in 5.1), 220 mg (50%) of methyl(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)propanoateare obtained in the form of a colorless oil.

7.2:(S)-2-(4-Methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)propanoicacid

In a manner analogous to example 3.7, using 220 mg (0.5 mmol) of methyl(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)propanoate,190 mg (90%) of(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)propanoicacid are obtained in the form of a white solid.

7.3:(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)propionamide

In a manner analogous to example 3.8, using 190 mg (0.4 mmol) of(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)propanoicacid, 30 mg (16%) of(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)propionamideare obtained in the form of a white solid with a melting point of 137°C.

¹H NMR (δ, DMSO): 0.91 (t, J=7.3 Hz, 3H); 1.63-1.73 (m, 2H); 2.45 (m,2H); 2.55 (m, 2H); 2.77 (s, 3H); 2.82 (m, 1H); 2.83-2.95 (m, 4H);2.95-3.05 (m, 2H); 3.94 (t, J=6.4 Hz, 2H); 7.03 (d, J=8.7 Hz, 2H); 7.38(m, 1H); 7.65 (d, J=8.7 Hz, 2H); 8.85 (s, 1H); 10.58 (s, 1H).

EXAMPLE 8(S)-3-[4-(3-Cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide

8.1: Methyl(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoate

In a manner analogous to example 5.2, using 205 mg (1 mmol) of3-(bromomethyl)benzonitrile and 400 mg (0.95 mmol) of methyl(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate(prepared as described in example 5.1), 295 mg (58%) of methyl(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoateare obtained in the form of a white solid.

8.2:(S)-3-[4-(3-Cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid

In a manner analogous to example 3.7, using 295 mg (0.5 mmol) of methyl(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoate,270 mg (94%) of(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid are obtained in the form of a white solid.

8.3:(S)-3-[4-(4-Cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide

In a manner analogous to example 3.8, using 264 mg (0.5 mmol) of(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid, 107 mg (40%) of(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamideare obtained in the form of a beige powder with a melting point of 108°C.

¹H NMR (δ, DMSO): 2.55 (m, 4H); 2.84 (s, 3H); 2.95-3.05 (m, 4H); 3.10(t, J=6.4 Hz, 1H); 3.34 (m; 2H); 5.26 (s, 2H); 7.22 (d, J=8.6 Hz, 2H);7.50 (s, 1H); 7.64 (t, J=7.6 Hz, 1H); 7.76 (d, J=8.6 Hz, 2H); 7.83 (t,J=8 Hz, 2H); 7.96 (s, 1H); 8.93 (s, 1H); 10.66 (s, 1H).

EXAMPLE 9(S)-3-[4-(4-Cyanobenzyloxy)benzenesulfonylamino]N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide9.1: Methyl(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoate

In a manner analogous to example 5.2, using 400 mg (1 mmol) of methyl(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate(prepared as described in 5.1) and 205 mg (1.1 mmol) of4-(bromomethyl)benzonitrile, 229 mg (45%) of methyl(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoateare obtained in the form of a white solid.

9.2:(S)-3-[4-(4-Cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid

In a manner analogous to example 3.7, using 229 mg (0.4 mmol) of methyl(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoate,

202 mg (91%)(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid are obtained in the form of a white solid.

9.3:(S)-3-[4-(4-Cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide

In a manner analogous to example 3.8, using 197 mg (0.4 mmol) of(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)-propanoicacid, 81 mg (40%) of(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamideare obtained in the form of a beige powder with a melting point of 109°C.

¹H NMR (δ, DMSO): 2.50-2.60 (m, 4H); 2.84 (s, 3H); 2.96 -3.01 (m, 4H);3.09 (t, J=7 Hz, 1H); 3.34 (s, 2H); 5.32 (s, 2H); 7.22 (d, J=8.8 Hz,2H); 7.50 (m, 1H); 7.66 (d, J=8.1 Hz, 2H); 7.75 (d, J=8.8 Hz, 2H); 7.89(d, J=8.1 Hz, 2H); 8.93 (s, 1H); 10.66 (s, 1H).

EXAMPLE 10 Benzyl4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]ethyl}piperazine-1-carboxylate10.1: Benzyl bis(2-chloroethyl)carbamate

13.2 ml (92 mmol) of benzyl chloroformate are added slowly to asolution, cooled to 0° C., of 15 g (84 mmol) of bis(2-chloroethylamine)hydrochloride, 26 ml (185 mmol) of triethylamine in 200 ml ofdichloromethane and 70 ml of tetrahydrofuran, stirred beforehand for 15min and then filtered in order to remove the triethylammonium chloride.The reaction medium is stirred at ambient temperature for 18 h. Afterthe addition of water, the reaction medium is extracted with ethylacetate. The organic phase is dried over magnesium sulfate, filtered andevaporated. 20 g of crude residue are obtained and purified bychromatography on silica gel, elution being carried out with an 8/2heptane/ethyl acetate mixture. 6 g (26%) of benzylbis(2-chloroethyl)carbamate are thus obtained.

10.2: Benzyl4-((S)-2-tert-butoxycarbonylamino-1-methoxycarbonylethyl)piperazine-1-carboxylate

A solution of 5.5 g (20 mmol) of benzyl bis(2-chloroethyl)carbamate and5.1 g (20 mmol) of methyl 2-amino-3-tert-butoxypropanoate hydrochloridein 40 ml of diisopropylethylamine is heated at 127° C. for 18 h. Aftercooling, the reaction medium is evaporated to dryness. 17 g of cruderesidue are obtained and purified by chromatography on silica gel,elution being carried out with a 9/1 up to 4/6 heptane/ethyl acetatemixture. 1.6 g (19%) of benzyl4-((S)-2-tert-butoxycarbonylamino-1-methoxycarbonylethyl)piperazine-1-carboxylate.

10.3: Benzyl 4-(2-amino-1-methoxycarbonylethyl)piperazine-1-carboxylatedihydrochloride

A solution of 1.45 g (3.4 mmol) of benzyl4-((S)-2-tert-butoxycarbonylamino-1-methoxycarbonylethyl)piperazine-1-carboxylatein 3.5 ml of a solution of hydrochloric acid in isopropanol, having aconcentration 5-6N, and 10 ml of methanol is heated at 40° C. for 3 hand then evaporated. The residue is taken up in diethyl ether andfiltered. 1.2 g (90%) of benzyl4-(2-amino-1-methoxycarbonylethyl)piperazine-1-carboxylatedihydrochloride are obtained in the form of a solid.

10.4: Benzyl4-[(S)-2-(4-hydroxybenzenesulfonylamino)-1-methoxycarbonylethyl]piperazine-1-carboxylate

2.1 ml (15 mmol) of triethylamine and then 920 mg (5 mmol) of4-hydroxybenzenesulfonyl chloride in 20 ml of dichloromethane are addeddropwise to a solution of 1.1 g (3 mmol) of benzyl4-(2-amino-1-methoxycarbonylethyl)piperazine-1-carboxylatedihydrochloride in 30 ml of dichloromethane, cooled beforehand to 0° C.The reaction medium is then stirred at ambient temperature for 18 h.After the addition of water, the reaction medium is extracted withdichloromethane. The organic phase is with water and then dried overmagnesium sulfate, filtered and concentrated under vacuum. The cruderesidue obtained is purified by chromatography on silica gel, elutionbeing carried out with a 50/50 heptane/ethyl acetate mixture. 60 mg(46%) of benzyl442-(4-hydroxybenzenesulfonylamino)-1-methoxycarbonylethyl]piperazine-1-carboxylateare obtained in the form of a white solid.

10.5: Benzyl4-{(S)-1-methoxycarbonyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzensulfonylamino]ethyl}piperazine-1-carboxylate

In a manner analogous to example 5.2, using 260 mg (1.4 mmol) of4-chloromethyl-2-methylquinoline and 600 mg (1.3 mmol) of benzyl4-[(S)-2-(4-hydroxybenzensulfonylamino)-1-methoxycarbonylethyl]piperazine-1-carboxylate,320 mg (40%) of benzyl4-{(S)-1-methoxycarbonyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]ethyl}piperazine-1-carboxylateare obtained in the form of a white solid.

10.6: Benzyl4-{(S)-1-carboxy-2-[4-(2-methylquinolin-4-ylmethoxybenzenesulfonylamino]ethyl}piperazine-1-carboxylate

In a manner analogous to example 3.7, using 160 mg (0.25 mmol) of benzyl4-{(S)-1-methoxycarbonyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]ethyl}piperazine-1-carboxylate,135 mg (87%) of benzyl4-{(S)-1-carboxy-2-[4-(2-methylquinolin-4-ylmethoxy-benzenesulfonylamino]ethyl}piperazine-1-carboxylateare obtained in the form of a beige solid.

10.7: Benzyl4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]ethyl}piperazine-1-carboxylate

In a manner analogous to example 3.8, using 135 mg (0.2 mmol) of benzyl4-{(S)-1-carboxy-2-[4-(2-methylquinolin-4-ylmethoxybenzenesulfonylamino]ethyl}piperazine-1-carboxylate,115 mg (82%) of benzyl4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]ethyl}piperazine-1-carboxylateare obtained in the form of a white solid with a melting point of 162°C.

¹H NMR (δ, DMSO): 2.35-2.45 (m, 4H); 2.70 (s, 3H); 2.80-2.90 (m, 1H);2.95-3.05 (m, 1H); 3.05-3.10 (m, 1H); 3.25-3.40 (m, 4H); 5.05 (s, 2H);5.74 (s, 2H); 7.29-7.40 (m, 7H); 7.55 (m, 1H); 7.60-7.70 (m, 2H); 7.79(d, J=8.8 Hz, 3H); 8.01 (d, J=8 Hz, 1H); 8.14 (d, J=8 Hz, 1H); 8.91 (s,1H); 10.67 (s, 1H).

EXAMPLE 11(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy)benzenesulfonylamino]propionamide11.1: Methyl(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy)benzenesulfonylamino]propanoate

0.23 ml (1.4 mmol) of diethyl azodicarboxylate is added slowly to asolution of 400 mg (0.9 mmol) of methyl(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate(prepared as described in example 5.1), 193 mg (1.0 mmol) of(2-phenylpyridin-4-yl)methanol and 373 mg (1.4 mmol) oftriphenylphosphine in 4 ml of tetrahydrofuran. The reaction mixture isstirred for one hour at ambient temperature and then evaporated todryness. The residue obtained is purified by chromatography on silicagel, elution being carried out with a 60/40 heptane/ethyl acetatemixture. 318 mg (57%) of methyl(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy)-benzenesulfonylamino]propanoateare obtained in the form of a white powder.

11.2:(S)-2-(4-Methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy)benzenesulfonylamino]propanoicacid

In a manner analogous to example 3.7, using 317 mg (0.5 mmol) of methyl(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy)benzenesulfonylamino]propanoate,298 mg (96%) of(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy)benzene-sulfonylamino]propanoicacid are obtained in the form of a white solid.

11.3:(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4)-(2-(2-phenylpyridin-4-ylmethoxy)benzenesulfonylamino]propionamide

In a manner analogous to example 3.8, using 293 mg (0.5 mmol) of(S)-2-(4-methane-sulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy)benzenesulfonylamino]propanoicacid, 64 mg (21%) of(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy)benzenesulfonylamino]propionamideare obtained in the form of a white powder with a melting point of 100°C.

¹H NMR (δ, DMSO): 2.52-2.59 (m, 4H); 2.84 (s, 3H); 2.85-2.90 (m, 1H);2.90-3.00 (m, 1H); 3.00-3.08 (m, 4H); 3.10 (t, J=7.0 Hz, 1H); 5.35 (s,2H); 7.26 (d, J=8.9 Hz, 2H); 7.42 (m, 1H); 7.45-7.55 (m, 4H); 7.78 (d,J=8.8 Hz, 2H); 8.03 (s, 1H); 8.10 (d, J=7.0 Hz, 2H); 8.69 (d, J=5.0 Hz,1H); 8.93 (s, 1H); 10.66 (s, 1H).

EXAMPLE 12(R)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide12.1: Methyl(R)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propanoate

In a manner analogous to example 3.2, using 3.8 g (17 mmol) ofN,N-bis(2-chloroethyl)-methanesulfonamide (prepared as described in 3.1)and 4 g (16 mmol) of commercial methyl(R)-2-amino-3-tert-butoxypropanoate hydrochloride, 2.6 g (46%) of methyl(R)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propanoateare obtained in the form of a light yellow solid.

12.2: Methyl (R)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoatedihydrochloride

In a manner analogous to example 3.3, using 2.5 g (7 mmol) of methyl(R)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propanoate,2.3 g (100%) of methyl(R)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate are obtained.

12.3: Methyl(R)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate

In a manner analogous to example 3.6, using 2.4 g (8.4 mmol) of4-benzyloxybenzenesulfonyl chloride (prepared as described in example3.5) and 2.3 g (7.6 mmol) of methyl(R)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoatedihydrochloride, 3 g (77%) of methyl(R)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoateare obtained in the form of a solid.

12.4: Methyl(R)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate

In a manner analogous to example 5.1, using 3 g (5.9 mmol) of methyl(R)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate,2 g (80%) of methyl(R)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoateare obtained in the form of a white solid.

12.5: Methyl(R)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmeth-oxy)benzenesulfonylamino]propanoate

In a manner analogous to example 5.2, using 1 g (2.4 mmol) of methyl(R)-3-(4-hydroxy-benzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoateand 500 mg (2.6 mmol) of 4-chloromethyl-2-methylquinoline, 740 mg (53%)of methyl(R)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoateare obtained in the form of a solid.

12.6:(R)-2-(4-Methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid

In a manner analogous to example 3.7, using 740 mg (1.3 mmol) of methyl(R)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate,622 mg (86%) of(R)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)-benzenesulfonylamino]propanoicacid are obtained.

12.7:(R)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

In a manner analogous to example 3.8, using 620 mg (1.1 mmol) of(R)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid, 465 mg (73%) of(R)-N-hydroxy-2-(4-methansulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamideare obtained in the form of a white solid.

¹H NMR (δ, DMSO): 2.53 (m, 4H); 2.68 (s, 3H); 2.84 (s, 3H); 2.85 (m,2H); 2.95-3.05 (m, 4H); 3.10 (m, 1H); 5.72 (s, 2H); 7.35 (d, J=8.8 Hz,2H); 7.52 (m, 1H); 7.57-7.62 (m, 2H); 7.75-7.82 (m, 3H); 7.98 (d, J=8.4Hz, 1H); 8.11 (d, J=8.16 Hz, 1H); 8.93 (s, 1H); 10.70 (s, 1H).

EXAMPLE 13(S)-N-Hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-piperazin-1-ylpropionamide13.1: Benzyl4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]ethyl}piperazine-1-carboxylate

In a manner analogous to example 3.8, using 135 mg (0.2 mmol) of benzyl4-{(S)-1-carboxy-2-[4-(2-methylquinolin-4-ylmethoxybenzenesulfonylamino]ethyl}piperazine-1-carboxylate(prepared as described in 10.6), 115mg (82%) of benzyl4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]ethyl}piperazine-1-carboxylateare obtained in the form of a white solid with a melting point of 162°C.

13.2:(S)-N-Hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-piperazin-1-ylpropionamide

90 mg (0.15 mmol) of benzyl4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]ethyl}piperazine-1-carboxylateare placed in solution in

5 ml of dichloromethane and 5 ml of trifluoroacetic acid. The reactionmedium is then stirred at ambient temperature for 96 h. Afterevaporation of the trifluoroacetic acid, the residue is taken up with 5ml of saturated aqueous solution of sodium hydrogen carbonate andextracted with n-butanol. The organic phase is washed with water andthen with a saturated aqueous solution of sodium chloride, dried overmagnesium sulfate, filtered and concentrated under vacuum. The crudeproduct obtained is taken up in a 50/50 heptane/ethyl acetate mixture,stirred for 1 h and then filtered and dried under vacuum. 50 mg (70%) of(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-piperazin-1-ylpropionamideare obtained in the form of a beige solid with a melting point of 225°C.

¹H NMR (δ, DMSO): 2.35-2.45 (m, 4H); 2.67 (s, 3H); 2.70 (m, 4H);2.80-3.00 (m, 2H); 3.15 (s, 1H); 5.72 (s, 2H); 7.35 (d, J=8.6 Hz, 2H);7.70-7.80 (m, 3H); 7.98 (d, J=8.4 Hz, 1H); 8.12 (d, J=8.2 Hz, 1H).

EXAMPLE 14(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamidehydrochloride

0.2 ml (1.3 mmol) of a solution of hydrochloric acid in isopropanolhaving a concentration of 5-6N is added to a solution of 301 mg (0.5mmol) of(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide(prepared as described in example 14) in 10 ml of isopropanol. Afterstirring at ambient temperature for 1 h, the product precipitates.Through filtration, 927 mg of(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamidehydrochloride are obtained in the form of a white powder. This solid isrecrystallized from a 30 ml/5 ml isopropanol/water mixture. 176 mg (52%)of(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamideare obtained in the form of a white powder with a melting point of 209°C.

¹H NMR (δ, DMSO): 2.67 (m, 4H); 2.87 (s, 3H); 2.93 (s, 3H); 3.00-3.15(m, 4H); 3.22 (m, 1H); 3.35-3.90 (m, 2H); 5.94 (s, 2H); 7.42 (d, J=8.7Hz, 2H); 7.64 (m, 1H); 7.83-7.90 (m, 3H); 7.98 (m, 1H); 8.05 (m, 1H);8.30 (d, J=7.6 Hz; 1H); 8.38 (d, J=8.5 Hz, 1H); 9.00 (m, 1H); 10.75 (m,1H).

EXAMPLE 15 tert-Butyl3-{4-[(S)-2-hydroxycarbamoyl-2-(4-methanesulfonylpiperazin-1-yl)ethylsulfamoyl]phenoxymethyl}-2-methylindole-1-carboxylatedi(trifluoroacetate). 15.1: tert-Butyl3-{4-[(S)-2-(4-methanesulfonylpiperazin-1-yl)-2-methoxycarbonylethylsulfamoyl]-phenoxymethyl}-2-methylindole-1-carboxylate

In a manner analogous to example 11.1, using 400 mg (0.95 mmol) ofmethyl(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate(prepared as described in example 5.1) and 248 mg (0.95 mmol) ofcommercial tert-butyl 3-hydroxymethyl-2-methylindole-1-carboxylate, 326mg (52%) of tert-butyl3-{4-[(S)-2-(4-methanesulfonylpiperazin-1-yl)-2-methoxycarbonylethylsulfamoyl]phenoxymethyl}-2-methylindole-1-carboxylateare obtained in the form of a beige powder.

15.2: tert-Butyl3-{4-[(S)-2-carboxy-2-(4-methanesulfonylpiperazin-1-yl)-ethylsulfamoyl]phenoxymethyl}-2-methylindole-1-carboxylate

In a manner analogous to example 3.7, using 325 mg (0.5 mmol) oftert-butyl3-{4-[(S)-2-(4-methanesulfonylpiperazin-1-yl)-2-methoxycarbonylethylsulfamoyl]phenoxymethyl}-2-methylindole-1-carboxylate,179 mg (100%) of tert-butyl3-{4-[(S)-2-carboxy-2-(4-methanesulfonylpiperazin-1-Aethylsulfamoyl]phenoxymethyl}-2-methylindole-1-carboxylateare obtained in the form of a yellow powder.

15.3: tert-Butyl3-{4-[(S)-2-hydroxycarbamoyl-2-(4-methanesulfonylpiperazin-1-yl)ethylsulfamoyl]phenoxymethyl}-2-methylindole-1-carboxylatedi(trifluoroacetate)

45 mg (0.3 mmol) of O-tert-butyldimethylsilylhydroxylamine in solutionin 1 ml of dimethylformamide are added to a solution of 179 mg (0.3mmol) of tert-butyl3-{4-[(S)-2-carboxy-2-(4-methanesulfonylpiperazin-1-yl)ethylsulfamoyl]phenoxymethyl}-2-methyl-indole-1-carboxylate,41 mg (0.3 mmol) of 1-hydroxybenzotriazole and 58 mg (0.3 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in 3 ml ofdimethylformamide. The reaction mixture is stirred at ambienttemperature for 18 h. After the addition of water and then extractionwith ethyl acetate, the organic phases are combined, washed with asaturated solution of sodium hydrogen carbonate and then dried oversodium sulfate, filtered and evaporated. The residue is purified bypreparative HPLC (Gemini C6 phenyl column, 150×3 mm, 3 μm; UV detector:190-420 nm; flow rate: 0.3 ml/mn; solvent A: CH₃CN+0.02% trifluoroaceticacid; solvent B: water+0.02% trifluoroacetic acid).

Gradient :

Time Composition  0.0 min A = 5%   B = 95% 20.0 min A = 98% B = 2% 30.0min A = 98% B = 2% Retention time: 14.6 min, M + 1 = 666.1.

After concentration of the various fractions, 21 mg (10%) of tert-butyl3-{4-[(S)-2-hydroxycarbamoyl-2-(4-methanesulfonylpiperazin-1-yl)ethylsulfamoyl]phenoxymethyl}-2-methylindole-1-carboxylatedi(trifluoroacetate) are obtained.

EXAMPLE 16(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzenesulfonylamino]propionamide.16.1: Methyl(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzenesulfonylamino]propanoate

In a manner analogous to example 5.2, using 440 mg (2.5 mmol) of4-chloromethylquinoline and 950 mg (2.2 mmol) of methyl(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate(prepared as described in 5.1), 550 mg (43%) of methyl(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzenesulfonylamino]propanoateare obtained in the form of a colorless oil.

16.2:(S)-2-(4-Methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid

In a manner analogous to example 3.7, using 550 mg (1.0 mmol) of methyl(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzenesulfonylamino]propanoate,450 mg (83%)(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzenesulfonylamino]-propanoicacid are obtained in the form of a white solid.

16.3:(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

In a manner analogous to example 3.8, using 450 mg (0.8 mmol) of(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid, 260 mg (56%) of(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzenesulfonylamino]propionamideare obtained in the form of a white solid with a melting point of 180°C.

¹H NMR (δ, DMSO): 2.52-2.54 (m, 4H); 2.84 (s, 3H); 2.87 (m, 1H); 2.97(m, 1H); 2.98-3.05 (m, 4H), 3.11 (t, J=7 Hz, 1H); 5.78 (s, 2H); 7.34 (d,J=8.8 Hz, 2H); 7.52 (m, 1H); 7.66-7.72 (m, 2H); 7.78-7.84 (m, 3H); 8.10(d, J=8.3 Hz, 1H); 8.19 (d, J=8.2 Hz, 1H); 8.93 (s, 1H); 8.94 (s, 1H);10.67 (s, 1H).

EXAMPLE 17(S)-2-(4-Benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

17.1: Sodium salt of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonicacid 100 g (438 mmol) of 4-chloromethyl-2-methylquinoline hydrochlorideare added to a solution of 77 g (395 mmol) of the sodium salt of4-hydroxybenzenesulfonic acid and of 84 ml (84 mmol) of an aqueoussolution of sodium hydroxide, having a concentration of 1M, in 800 ml ofisopropanol. The reaction medium is heated at 70° C. for 5 h and then at40° C. for 18 h.

After evaporation of the isopropanol, the product obtained is filtered,rinsed with isopropanol and with diethyl ether and then dried undervacuum. 114 g (75%) of the sodium salt of4-(2-methylquinolin-4-ylmethoxy)benzenesulfonic acid are obtained in theform of a white solid.

17.2: 4-(2-Methylquinolin-4-ylmethoxy)benzenesulfonyl chloride

76 g (216 mmol) of the sodium salt of4-(2-methylquinolin-4-ylmethoxy)benzenesulfonic acid in 500 ml ofdimethylformamide are added dropwise to a solution of 55 ml (649 mmol)of oxalyl chloride in 100 ml of dichloromethane, cooled beforehand to-10° C. After the addition, the reaction medium is stirred at ambienttemperature for 18 h. The reaction medium is then poured into 1 I of iceand then extracted with ethyl acetate. The organic phases are combined,washed with water and then with a saturated aqueous solution of sodiumchloride, dried over magnesium sulfate, filtered and concentrated undervacuum. 77 g (92%) of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylchloride hydrochloride are obtained in the form of a beige solid.

17.3: Benzylbis(2-chloroethyl)amine

21 g (152 mmol) of potassium carbonate and then 8 ml (67 mmol) of benzylbromide are added to a solution of 10 g (56 mmol) ofbis(2-chloroethyl)amine hydrochloride in 130 ml of acetonitrile, andthen the reaction medium is heated at 60° C. for 24 h. After filtration,the filtrate is concentrated under vacuum. The crude residue is purifiedby chromatography on silica gel, elution being carried out with a 90/10heptane/ethyl acetate mixture, to give 8.5 g (65%) ofbenzylbis(2-chloroethyl)amine.

17.4: Methyl(S)-2-(4-benzylpiperazin-1-yl)-3-tert-butoxycarbonylaminopropanoate

A solution of 5.9 g (23 mmol) of commercial methyl(S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and of9.6 g (23 mmol) of benzylbis(2-chloroethyl)amine in 50 ml ofN,N-diisopropylethylamine is heated at 127° C. for 3h 30. Afterevaporation of the N,N-diisopropylethylamine, the reaction medium ishydrolyzed and then extracted with ethyl acetate. The organic phase iswashed with an aqueous solution of sodium hydroxide having aconcentration of 1N, and with water, and then dried over magnesiumsulfate, filtered and concentrated under vacuum. The crude productobtained is purified by chromatography on silica gel, elution beingcarried out with a 50/50 heptane/ethyl acetate mixture. 8.9 g (64%) ofmethyl(S)-2-(4-benzylpiperazin-1-yl)-3-tert-butoxycarbonylaminopropanoate areobtained in the form of a yellow oil.

17.5: Methyl (S)-3-amino-2-(4-benzylpiperazin-1-yl)propanoatetrihydrochloride

8.9 g (23.5 mmol) of methyl(S)-2-(4-benzylpiperazin-1-yl)-3-tert-butoxycarbonylaminopropanoate areplaced in solution in 60 ml of methanol and in 20 ml of isopropanolichydrochloric acid having a concentration of 5-6N. The reaction medium isstirred at 40° C. for 18 h and then concentrated under vacuum. 9.0 g(100%) of methyl (S)-3-amino-2-(4-benzylpiperazin-1-yl)propanoatetrihydrochloride are obtained in the form of a beige solid.

17.6: Methyl(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate

In a manner analogous to example 3.6, using 1.0 g (2.6 mmol) of methyl(S)-3-amino-2-(4-benzylpiperazin-1-yl)propanoate trihydrochloride and1.1 g (2.8 mmol) of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylchloride in hydrochloride form, 750 mg (50%) of methyl(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoateare obtained in the form a beige solid.

17.7:(S)-2-(4-Benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid

In a manner analogous to example 3.7, using 750 mg (1.3 mmol) of methyl(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate,680 mg (93%) of(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid are obtained in the form of a white solid.

17.8:(S)-2-(4-Benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

In a manner analogous to example 3.8, using 680 mg (1.2 mmol) of(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid, 250 mg (36%) of(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamideare obtained in the form of a white solid with a melting point of 188°C.

¹H NMR (δ, DMSO): 2.33 (m, 4H); 2.49 (m, 4H); 2.73 (s, 3H); 2.80-2.90(m, 1H); 3.00-3.10 (m, 2H); 2.46 (m, 2H); 5.77 (s, 2H); 7.25-7.40 (m,7H); 7.50(m, 1H); 7.61-7.67 (m, 2H); 7.78-7.85 (m, 3H); 8.04 (d, J=8 Hz,1H); 8.17 (d, J=8.2 Hz, 1H); 8.95 (s, 1H); 10.65 (s, 1H).

EXAMPLE 18(S)-2-[4-(4-Fluorobenzyl)piperazin-1-yl]-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide18.1: Bis(2-chloroethyl)(4-fluorobenzyl)amine

In a manner analogous to example 17.3, using 5 g (28 mmol) ofbis(2-chloroethyl)amine hydrochloride and 3.8 ml (31 mmol) of1-bromomethyl-4-fluorobenzene, 6.9 g (98%) ofbis(2-chloroethyl)(4-fluorobenzyl)amine are obtained.

18.2: Methyl(S)-3-tert-butoxycarbonylamino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoate

In a manner analogous to example 17.4, using 7.1 g (28 mmol) of methyl(S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and 6.9 g(28 mmol) of bis(2-chloroethyl) (4-fluorobenzyl)amine, 5.3 g (48%) ofmethyl(S)-3-tert-butoxycarbonylamino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoateare obtained in the form of an oil.

18.3: Methyl (S)-3-amino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoatetrihydrochloride

In a manner analogous to example 17.5, using 5.3 g (13.4 mmol) of methyl(S)-3-tert-butoxycarbonylamino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoate,5.4 g (100%) of methyl(S)-3-amino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoatetrihydrochloride are obtained in the form of a beige solid.

18.4: Methyl(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate

In a manner analogous to example 3.6, using 1.5 g (3.7 mmol) of methyl(S)-3-amino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoatetrihydrochloride and 1.6 g (4.1mmol) of4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride hydrochloride(prepared as described in 17.2), 1.0 g (46%) of methyl(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoateis obtained in the form of a white solid.

18.5:(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid

In a manner analogous to example 3.7, using 1.1 g (1.7 mmol) of methyl(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate,1.0 g (100%) of(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzene-sulfonylamino]propanoicacid are obtained in the form of a white solid.

18.6:(S)-2-[4-(4-Fluorobenzyl)piperazin-1-yl]-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

In a manner analogous to example 3.8, using 990 mg (1.7 mmol) of(S)-2-[4-(4-fluorobenzyl)-piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid, 330 mg (33%) of(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzene-sulfonylamino]propionamideare obtained in the form of a white solid with a melting point of 180°C.

¹H NMR (δ, DMSO): 2.20-2.30 (m, 4H); 2.35-2.45 (m, 4H); 2.66 (s, 3H);2.72-2.80 (m, 1H); 2.87-3.00 (m, 2H); 3.38 (s, 2H); 5.70 (s, 2H); 7.10(t, J=8.8 Hz, 2H); 7.26-7.33 (m, 4H); 7.56-7.60(m, 2H); 7.73-7.78 (m,3H); 7.97 (d, J=8.4 Hz, 1H); 8.10 (d, J=8,2 Hz, 1H).

EXAMPLE 19(S)-2-(4-ethyl-piperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-yl-methoxy)benzenesulfonylamino]propionamide19.1: bis(2-Chloroethyl)ethylamine

24 ml (330 mmol) of thionyl chloride are added dropwise to a solution of20 g (150 mmol) of 2-[ethyl(2-hydroxyethyl)amino]ethanol in 200 ml ofdichloromethane cooled beforehand to 0° C., and then the reaction mediumis stirred at ambient temperature for 20 h. After the addition of asaturated aqueous solution of sodium hydrogen carbonate, the product isextracted with dichloromethane. The organic phase obtained is thenwashed with water, dried over magnesium sulfate, filtered andconcentrated under vacuum. 19.5 g (76%) of bis(2-chloroethyl)ethylamineare obtained in the form of an oil.

19.2: Methyl(S)-3-tert-butoxycarbonylamino-2-(4-ethylpiperazin-1-yl)propanoate

A solution of 5.0 g (19.6 mmol) of commercial methyl(S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and 3.3 g(19.6 mmol) of bis(2-chloroethyl)ethylamine in 50 ml ofN,N-diisopropylethylamine is heated at 127° C. for 5 h.

After evaporation of a maximum amount of diisopropylethylamine, thereaction medium is diluted with ethyl acetate and washed with an aqueoussolution of sodium hydroxide having a concentration of 1 N. The organicphase obtained is then washed with water, dried over magnesium sulfate,filtered and concentrated under vacuum. The crude product obtained ispurified by chromatography on silica gel, elution being carried out witha 30/70 heptane/ethyl acetate mixture. 2.5 g (40%) of methyl(S)-3-tert-butoxycarbonylamino-2-(4-ethylpiperazin-1-yl)propanoate areobtained in the form of an oil.

19.3: Methyl (S)-3-amino-2-(4-ethylpiperazin-1-yl)propanoatetrihydrochloride

2.5 g (7.9 mmol) of methyl(S)-3-tert-butoxycarbonylamino-2-(4-ethylpiperazin-1-yl)propanoate areplaced in 20 ml of methanol and 10 ml of isopropanolic hydrochloric acidhaving a concentration of 5-6N. The reaction medium is heated at 40° C.for 3 h and then evaporated to dryness. The residue is taken up in 50 mlof ethanol, stirred for 1 h at ambient temperature and then filtered.1.4 g (54%) of methyl (S)-3-amino-2-(4-ethylpiperazin-1-yl)propanoatetrihydrochloride are obtained in the form of a beige solid.

19.4: Methyl(S)-2-(4-ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate

In a manner analogous to example 3.6, using 700 mg (2.1 mmol) of methyl(S)-3-amino-2-(4-ethylpiperazin-1-yl)propanoate trihydrochloride and 900mg (2.3 mmol) of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylchloride hydrochloride (prepared as described in 17.2), 740 mg (67%) ofmethyl(S)-2-(4-ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoateare obtained in the form of a white solid.

19.5:(S)-2-(4-Ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid

In a manner analogous to example 3.7, using 740 mg (1.4 mmol) of methyl(S)-2-(4-ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate,630 mg (87%) of(S)-2-(4-ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid are obtained in the form of a white solid.

19.6:(S)-2-(4-Ethylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

In a manner analogous to example 3.8, using 630 mg (1.2 mmol) of(S)-2-(4-ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid, 60 mg (8%) of(S)-2-(4-ethylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamideare obtained in the form of a white solid with a melting point of 150°C.

¹H NMR (δ, DMSO): 2.49 (s, 3H); 2.55-2.65 (m, 2H); 2.69 (s, 3H);2.70-2.90 (m, 6H); 2.90-3.00 (m, 2H); 3.13 (t, J=7.3 Hz, 1H); 3.20-3.35(m, 2H); 3.36 (s, 2H); 5.72 (s, 2H); 7.35 (d, J=8.9 Hz, 2H); 7.58-7.62(m, 3H); 7.74-7.81 (m, 3H); 7.98 (d, J=7.9 Hz, 1H); 8.12 (d, J=8.3 Hz,1H); 9.03 (s, 1H), 10.82 (s, 1H).

EXAMPLE 20(S)-N-Hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propionamide20.1: bis-(2-Chloroethyl)(4-trifluoromethylbenzyl)amine

In a manner analogous to example 32.3, using 5.0 g (28 mmol) ofbis(2-chloroethyl)amine hydrochloride and 7.4 g (31 mmol) of1-bromomethyl-4-trifluoromethylbenzene, 5 g (59%) of abis(2-chloroethyl)(4-trifluoromethylbenzyl)amine mixture are obtained inthe form of a colorless oil.

20.2: Methyl(S)-3-tert-butoxycarbonylamino-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propanoate

A solution of 4.2 g (16.5 mmol) of methyl(S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and 4.95g (16.5 mmol) of bis(2-chloroethyl)(4-trifluoromethylbenzyl)amine in 25ml of N,N-diisopropylethylamine is heated at 127° C. for 6 h. Afterevaporation of a maximum amount of diisopropylethylamine, the reactionmedium is diluted with ethyl acetate and washed with an aqueous solutionof sodium hydroxide having a concentration of 1N. The organic phaseobtained is washed with water, dried over magnesium sulfate, filteredand concentrated under vacuum. The crude residue is purified bychromatography on silica gel, elution being carried out with a 60/40heptane/ethyl acetate mixture. 4.0 g (55%) of methyl(S)-3-tert-butoxycarbonylamino-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propanoateare obtained in the form of an oil.

20.3: Methyl(S)-3-amino-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propanoatetrihydrochloride

In a manner analogous to example 17.5, using 4 g (9.1 mmol) of methyl(S)-3-tert-butoxycarbonylamino-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propanoate,3.8 g (93%) of methyl(S)-3-amino-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propanoate areobtained in the form of a beige solid.

20.4: Methyl(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propanoate

In a manner analogous to example 3.6, using 1.0 g (2.2 mmol) of methyl(S)-3-amino-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propanoatetrihydrochloride and 1.2 g (3.1 mmol) of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride hydrochloride (prepared as described inexample 17.2), 910 mg (65%) of methyl(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propanoateare obtained in the form of a white solid.

20.5:(S)-3-[4-(2-Methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propanoicacid

In a manner analogous to example 3.7, using 910 mg (1.4 mmol) of methyl(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]-propanoate,790 mg (88%) of(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trifluoromethylbenzyl)-piperazin-1-yl]propanoicacid are obtained in the form of a white solid.

20.6:S)-N-Hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propionamide

In a manner analogous to example 3.8, using 790 mg (1.2 mmol) of(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propanoicacid, 550 mg (68%) of(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trifluoro-methylbenzyl)piperazin-1-yl]propionamideare obtained in the form of a white solid with a melting point of 148°C.

¹H NMR (δ, DMSO): 2.21 (m, 4H); 2.38 (m, 4H); 2.58 (s, 3H); 2.69-2.75(m, 1H); 2.85-2.93 (m, 1H); 2.93-2.98 (m, 1H); 3.42 (s, 2H); 5.63 (s,2H); 7.25 (d, J=9 Hz, 2H); 7.40 (d, J=8 Hz, 3H); 7.47-7.53 (m, 2H); 7.57(d, J=8.1 Hz, 2H); 7.65-7.72 (m, 3H); 7.90 (d, J=7.9 Hz, 1H); 8.03 (d,J=7.8 Hz, 1H); 8.83 (s, 1H), 10.56 (s, 1H).

EXAMPLE 21(S)-N-hydroxy-2-[44-(4-methylbenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide21.1: bis(2-Chloroethyl)(4-methylbenzyl)amine

In a manner analogous to example 17.3, using 5.0 g (28 mmol) ofbis(2-chloroethyl)amine hydrochloride and 5.7 g (31 mmol) of1-bromomethyl-4-methylbenzene, 4.9 g (71%) ofbis(2-chloroethyl)(4-methylbenzyl)amine are obtained.

21.2: Methyl(S)-3-tert-butoxycarbonylamino-2-[4-(4-methylbenzyl)piperazin-1-yl]propanoate

In a manner analogous to example 17.4, using 5.1 g (20 mmol) ofcommercial methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoatehydrochloride and 4.9 g (20 mmol) ofbis(2-chloroethyl)(4-methylbenzyl)amine, 4.1 g (53%) of methyl(S)-3-tert-butoxycarbonylamino-2-[4-(4-methylbenzyl)piperazin-1-yl]propanoateare obtained in the form of an oil.

21.3: Methyl (S)-3-amino-2-[4-(4-methylbenzyl)piperazin-1-yl]propanoatetrihydrochloride

In a manner analogous to example 19.3, using 4.1 g (10,5 mmol) of methyl(S)-3-tert-butoxycarbonylamino-2-[4-(4-methylbenzyl)piperazin-1-yl]propanoate,3.95 g (94%) of methyl(S)-3-amino-2-[4-(4-methylbenzyl)piperazin-1-yl]propanoatetrihydrochloride are obtained in the form of a cream solid.

21.4: Methyl(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-methylbenzyl)piperazin-1-yl]propanoate

In a manner analogous to example 3.6, using 1.0 g (2.5 mmol) of methyl(S)-3-amino-2-[4-(4-methylbenzyl)piperazin-1-yl]propanoatetrihydrochloride and 1.3 g (3.5 mmol) of4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride hydrochloride(prepared as described in example 17.2), 950 mg (63%) of methyl(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-methylbenzyl)piperazin-1-yl]propanoateare obtained in the form of a white solid.

21.5:(S)-2-[4-(4-Methylbenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid

In a manner analogous to example 3.7, using 950 mg (1.6 mmol) of methyl(S)-2-[4-(4-methylbenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate,880 mg (95%) of(S)-2-[4-(4-methylbenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid are obtained in the form of a cream solid.

21.6:(S)-N-Hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-methylbenzyl)piperazin-1-yl]propionamide

In a manner analogous to example 3.8, using 880 mg (1,5 mmol) of(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-methylbenzyl)piperazin-1-yl]propanoicacid, 150 mg (17%) of(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-methylbenzyl)piperazin-1-yl]propionamideare obtained in the form of a white solid with a melting point of 170°C.

¹H NMR (δ, DMSO): 2.25 (m, 4H); 2.25 (s, 3H); 2.43 (m, 4H); 2.67 (s,3H); 2.80 (m, 1H); 2.95-3.05 (m, 2H); 3.37 (m, 2H); 5.71 (s, 2H); 7.10(q, J=8 Hz, 4H); 7.33 (d, J=8.9 Hz, 2H); 7.43 (m, 1H); 7.56-7.61 (m,2H); 7.73-7.79 (m, 3H); 7.98 (d, J=8.3 Hz, 1H); 8.11 (d, J=8.2 Hz, 1H);8.89 (s, 1H); 10.59 (s, 1H).

EXAMPLE 22(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide22.1: Benzoisoxazol-3-ylmethanol

589 mg (3.0 mmol) of ethyl 1.2-benzoisoxazole-3-carboxylate in solutionin 10 ml of tetrahydrofuran are added to a suspension of 129 mg (3.5mmol) of lithium aluminum hydride in 5 ml of tetrahydrofuran. Thereaction mixture is stirred for one hour at 60° C. and then treated byadding 2 ml of methanol dropwise, filtered through celite and rinsedwith ethyl acetate. The organic phases are combined, dried over sodiumsulfate and evaporated. The residue obtained is purified bychromatography on silica gel, elution being carried out with a 60/40heptane/ethyl acetate mixture. 180 mg (39%) ofbenzoisoxazol-3-ylmethanol are obtained in the form of a white solid.

22.2: Methyl(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoate

In a manner analogous to example 11.1, using 494 mg (1.2 mmol) of methyl(S)-3-(4-hydroxy-benzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate(prepared as described in 5.1) and 175 mg (1.2 mmol) ofbenzoisoxazol-3-ylmethanol, 459 mg (71%) of methyl(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoateare obtained in the form of an oil.

22.3:(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid

In a manner analogous to example 3.7, using 458 mg (0.8 mmol) of methyl(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoate,283 mg (63%) of(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoicacid are obtained in the form of a white solid.

22.4:(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide

In a manner analogous to example 3.8, using 283 mg (0.5 mmol) of(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-ethanesulfonylpiperazin-1-yl)propanoicacid, 231 mg (80%) of(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamideare obtained in the form of a beige solid with a melting point of 107°C.

¹H NMR (δ, DMSO): 2.53-2.55 (m, 4H); 2.88 (s, 3H); 2.90-2.93 (m, 2H);3.00-3.10 (m, 4H); 3.13 (t, J=6.9 Hz,1H); 5.77 (s, 2H); 7.35 (d, J=8.8Hz, 2H); 7.49 (t, J=7.5 Hz, 1H); 7.57 (m, 1H); 7.75 (t, J=7.4 Hz, 1H);7.78-7.87 (m, 3H); 8.01 (d, J=8 Hz, 1H); 8.96 (m, 1H); 10.67 (m, 1H).

EXAMPLE 23(S)-N-hydroxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)-benzenesulfonylamino]propionamide.23.1: Methyl (S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate

2 g (25% by weight) of palladium-on-carbon at 10% are added to asolution of 8 g (21 mmol) ofmethyl(S)-2-(4-benzylpiperazin-1-yl)-3-tert-butoxycarbonylaminopropanoate(prepared as described in example 17.4) in 120 ml of ethanol, degassedbeforehand under a nitrogen stream. The reaction medium is then placedunder a hydrogen atmospheric pressure for 24 h and then filtered throughcelite and thoroughly rinsed with dichloromethane. After concentrationunder vacuum, 6.1 g (100%) of methyl(S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate are obtained.

23.2: Methyl(S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoate

1.2 ml (8.3 mmol) of triethylamine and then 0.8 ml (7.6 mmol) ofisobutyryl chloride are added to a solution of 2.0 g (6.9 mmol) ofmethyl (S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate in 20ml of dichloromethane, cooled beforehand to 0° C. After stirring atambient temperature for 1 h 30, water is added. The reaction medium isextracted with dichloromethane. The organic phase is washed with water,dried over magnesium sulfate, filtered and concentrated under vacuum.The crude residue obtained is purified by chromatography on silica gel,elution being carried out with a 50/50 heptane/ethyl acetate mixture.2.0g (81%) of methyl(S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoateare obtained in the form of a colorless oil.

23.3:(S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoicacid

10 ml (10 mmol) of an aqueous solution of lithium hydroxide having aconcentration of 1N are added to a solution of 2.0 g (5.6 mmol) ofmethyl(S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoatein 40 ml of tetrahydrofuran and 8 ml of water, and then the reactionmedium is stirred at ambient temperature for 20 h. After the addition ofan aqueous solution of acetic acid having a concentration of 1N, theproduct is extracted with n-butanol. The organic phase is dried overmagnesium sulfate, filtered and concentrated under vacuum, 1.5 g (78%)of(S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoicacid are obtained in the form of a white solid.

23.4: tert-Butyl[(S)-2-allyloxycarbamoyl-2-(4-isobutyrylpiperazin-1-yl)ethyl]carbamate

1.4 g (4.4 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate and then 2.3 ml (13.1mmol) of diisopropylethylamine are added to a solution of 1.5 g (4.4mmol) of(S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoicacid in 20 ml of dimethylformamide. After stirring at ambienttemperature for 15 min, a solution of 500 mg (4.6 mmol) of0-allylhydroxylamine hydrochloride and of 0.8 ml (4.6 mmol) ofdiisopropylethylamine in 10 ml of dimethylformamide is added. Thereaction medium is stirred at ambient temperature for 20 h, hydrolyzedwith a saturated aqueous solution of sodium hydrogen carbonate, and thendiluted with ethyl acetate. The organic phase is washed with a saturatedaqueous solution of sodium chloride, dried over magnesium sulfate,filtered and concentrated under vacuum, 1.45 g (83%) of tert-butyl[(S)-2-allyloxycarbamoyl-2-(4-isobutyrylpiperazin-1-yl)ethyl]carbamateare obtained in the form of a colorless oil.

23.5: (S)-N-allyloxy-3-amino-2-(4-isobutyrylpiperazin-1-yl)propionamidedihydrochloride

In a manner analogous to example 19.3, using 1.45 g (3.6 mmol) oftert-butyl[(S)-2-allyloxycarbamoyl-2-(4-isobutyrylpiperazin-1-yl)ethyl]carbamate,1.4 g (100%) of(S)-N-allyloxy-3-amino-2-(4-isobutyrylpiperazin-1-yl)propionamidedihydrochloride are obtained in the form of a white solid.

23.6:(S)-N-allyloxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

1.9 g (5.1 mmol) of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylchloride hydrochloride (prepared as described in 32.2) are added to asolution of 1.3 g (3.6 mmol) of(S)-N-allyloxy-3-amino-2-(4-isobutyrylpiperazin-1-yl)propionamidedihydrochloride, 2.0 ml (14.5 mmol) of triethylamine in 15 ml ofdichloromethane and 15 ml of dimethylformamide, cooled beforehand to 0°C. The reaction medium is then stirred at from 0° C. to ambienttemperature over the course of 3 h. After the addition of water, thereaction medium is extracted with dichloromethane. The organic phase iswashed with a saturated aqueous solution of sodium hydrogen carbonateand with water, dried over magnesium sulfate, filtered and concentrated.

The crude residue obtained is purified by silica column chromatography,elution being carried out with a 97/3 dichloromethane/methanol mixture.900 mg (41%) of(S)-N-allyloxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamideare obtained in the form of a white solid.

23.7:(S)-N-hydroxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)-benzenesulfonylamino]propionamide

33 mg (0.06 mmol) of tetrakis(triphenylphosphine)palladium and then 920mg (6.6 mmol) of potassium carbamate are added to a solution of 670 mg(1.1 mmol) of(S)-N-allyloxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamidein 15 ml of methanol and then the reaction medium is refluxed for 8 h.After the addition of ethyl acetate, the reaction medium is washed witha saturated aqueous solution of sodium hydrogen carbonate. The organicphase is then washed with water, dried over magnesium sulfate. filteredand concentrated. The crude product is taken up in 6 ml of ethanol and12 ml of water and then heated at 80° C. until solubilization occurs.After cooling, crystallization is initiated by evaporation of a minimumamount of ethanol. 120 mg of product are obtained by filtration and arepurified by preparative thin layer chromatography on silica, elutionbeing carried out with a 97/3 dichloromethane/methanol mixture.

20 mg (3%) of(S)-N-hydroxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-yl-methoxy)benzenesulfonylamino]propionamideare finally obtained in the form of a beige solid.

¹H NMR (δ, DMSO): 0.84 (s, 3H); 0.85 (s, 3H); 2.30-2.44 (m, 2H); 2.52(m, 2H); 2.67 (s, 3H); 2.77 (m, 1H); 2.85 (m, 2H); 2.95 (m, 1H); 3.35(m, 4H); 5.71 (s, 2H); 7.33 (d, J=8.9 Hz, 2H); 7.43 (m, 1H); 7.55-7.62(m, 2H); 7.72-7.82 (m, 3H); 7.98 (d, J=8.4 Hz, 1H); 8.11 (d, J=8.2 Hz,1H); 8.96 (m, 1H); 10.67 (m, 1H).

EXAMPLE 24(S)-N-hydroxy-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide24.1: Methyl(S)-3-tert-butoxycarbonylamino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]propanoate

479 mg (3.0 mmol) of 2-methylpropane-1-sulfonyl chloride are added to asolution of 800 mg (2.8 mmol) of methyl(S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate (prepared asdescribed in example 23.1) and 775 pl (5.5 mmol) of triethylamine in 8ml of dichloromethane, cooled beforehand to 0° C. The reaction medium isstirred at ambient temperature for 18 h and then water is added and themedium is extracted with dichloromethane. The organic phase is washedwith water, dried over magnesium sulfate, filtered and concentrated. Theresidue obtained is purified by chromatography on silica gel, elutionbeing carried out with a 5/5 heptane/ethyl acetate mixture. 785 mg (71%)of methyl(S)-3-tert-butoxycarbonylamino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]propanoateare obtained in the form of a colorless oil.

24.2: Methyl(S)-3-amino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]propanoatedihydrochloride

In a manner analogous to example 3.3, using 785 mg (1.9 mmol) of methyl(S)-3-tert-butoxycarbonylamino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]propanoate,621 mg (85%) of methyl(S)-3-amino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]propanoatedihydrochloride are obtained in the form of a solid.

24.3: Methyl(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate

In a manner analogous to example 3.6, using 621 mg (1.6 mmol) of methyl(S)-3-amino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]propanoatedihydrochloride and 876 mg (2.3 mmol) of4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride hydrochloride(prepared as described in example 17.2), 643 mg (64%) of methyl(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoateare obtained in the form of an oil.

24.4:(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid

In a manner analogous to example 3.7, using 643 mg (1.0 mmol) of methyl(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate,395 mg (63%) of(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid are obtained in the form of a white solid.

24.5:(S)-N-hydroxy-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide

In a manner analogous to example 3.8, using 390 mg (0.6 mmol) of(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoicacid, 12 mg (3%) of(S)-N-hydroxy-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamideare obtained in the form of a white solid.

¹H NMR (δ, DMSO): 1.01 (d, J=6.7 Hz, 6H); 2.05 (m, 1H); 2.49 (m, 4H);2.67 (s, 3H); 2.86 (d, J=6.6 Hz, 2H); 3.00-3.10 (m, 6H); 3.31 (m, 1H);5.71 (s, 2H); 7.34 (d, J=8.9 Hz, 2H); 7.52 (m, 1H); 7.57 (m, 2H);7.76-7.80 (m, 3H); 7.98 (d, J=8.2 Hz, 1H); 8.10 (m, 1H); 8.93 (s, 1H);10.66 (s, 1H).

EXAMPLE 25(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethyl-pyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide25.1: Ethyl 2-trifluoromethylpyrazolo[1,5-α]pyridine-3-carboxylate

A solution of 2.1 g (38 mmol) of KOH in 20 ml of water and then 6.7 g(30 mmol) of 1-aminopyridinium iodide are added to a solution of 2.5 g(15 mmol) of ethyl 4,4,4-trifluorobut-2-ynoate in 25 ml ofdichloromethane. After stirring at ambient temperature for 5 h, water isadded and the reaction medium is extracted with dichloromethane. Theorganic phase is washed with water, dried over magnesium sulfate.filtered and concentrated. The residue obtained is purified bychromatography on silica gel, elution being carried out with an 8/2heptane/ethyl acetate mixture. 2.8 g (73%) of ethyl2-trifluoromethylpyrazolo[1,5-α]pyridine-3-carboxylate are obtained inthe form of a yellow solid.

25.2: (2-trifluoromethylpyrazolo[1,5-α]pyridin-3-yl)methanol

A solution of 2.8 g (11 mmol) of ethyl2-trifluoromethylpyrazolo[1,5-α]pyridine-3-carboxylate in 50 ml oftetrahydrofuran is added dropwise to a suspension of 0.5 g (12 mmol) oflithium aluminum hydride in 45 ml of tetrahydrofuran. The reactionmedium is then stirred at 70° C. for 3 h. After dropwise addition of 2.5ml of methanol and then of 1.8 ml of an aqueous solution of sodiumhydroxide having a concentration of 2N, the reaction medium is stirredfor 20 min at ambient temperature and then filtered. The filtrate isdried over magnesium sulfate, filtered and concentrated under vacuum.2.3 g (100%) of (2-trifluoromethylpyrazolo[1,5-α]pyridin-3-yl)methanolare obtained in the form of a solid.

25.3: Methyl(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoate

In a manner analogous to example 11.1, using 800 mg (1.9 mmol) of methyl(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate(prepared as described in 5.1) and 540 mg (2.5 mmol) of(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-yl)methanol, 380 mg (32%) ofmethyl(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoateare obtained in the form of a white solid.

25.4:(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoicacid

In a manner analogous to example 3.7, using 380 mg (0.6 mmol) of methyl(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoate,237 mg (64%) of(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoicacid are obtained in the form of a white solid.

25.5:(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide

In a manner analogous to example 3.8, using 230 mg (0.4 mmol) of(S)-2-(4-methanesulfonyl-piperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoicacid, 9 mg (4%) of(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamideare obtained in the form of a white solid.

¹H NMR (a, DMSO): 2.51-2.54 (m, 4H); 2.84 (s, 3H); 2.95 (m, 1H);2.97-3.04 (m, 4H); 3.10 (m, 1H); 3.32 (m, 1H); 5.45 (s, 2H); 7.20-7.25(m, 3H); 7.49-7.51 (m, 2H); 7.76 (d, J=8.8 Hz, 2H); 8.04 (m, 1H); 8.87(d, J=7 Hz, 2H); 8.90 (m, 1H).

EXAMPLE 26(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propionamide26.1: Methyl(S)-3-tert-butoxycarbonylamino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoate

In a manner analogous to example 20.2, using 800 mg (2.8 mmol) of methyl(S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate (prepared asdescribed in example 23.1) and 342 pl (3.1 mmol) of propane-2-sulfonylchloride, 700 mg (64%) of methyl(S)-3-tert-butoxycarbonylamino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoateare obtained in the form of an oil.

26.2: Methyl(S)-3-amino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoatedihydrochloride

In a manner analogous to example 3.3, using 700 mg (1.8 mmol) of methyl(S)-3-tert-butoxycarbonylamino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoate,620 mg (86%) of methyl(S)-3-amino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoatedihydrochloride are obtained in the form of an oil.

26.3: Methyl(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoate

In a manner analogous to example 17.6, using 620 mg (1.5 mmol) of methyl(S)-3-amino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoatedihydrochloride and 830 mg (2.1 mmol) of4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride hydrochloride(prepared as described in the example 17.2), 505 mg (54%) of methyl(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoateare obtained in the form of a white solid.

26.4:(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoicacid

In a manner analogous to example 3.7, using 505 mg (0.8 mmol) of methyl(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoate,135 mg (27%) of(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoicacid are obtained in the form of a white solid.

26.5:(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propionamide

In a manner analogous to example 3.8, using 135 mg (0.2 mmol) of(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoicacid, 24 mg (17%) of(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propionamideare obtained in the form of a white solid.

¹H NMR (δ, DMSO): 1.19 (d, J=6.8 Hz, 6H); 2.45 (m, 4H); 2.68 (s, 3H);2.80-2.90 (m, 1H); 2.95-3.15 (m, 6H); 3.29 (m, 1H); 5.72 (s, 2H); 7.34(d, J=8.9 Hz, 2H); 7.52 (m, 1H); 7.57 (m, 2H); 7.76-7.80 (m, 3H); 7.98(d, J=8.2 Hz, 1H); 8.10 (d, J=8.1 Hz, 1H); 8.93 (s, 1H); 10.66 (s, 1H).

EXAMPLE 27(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide27.1: 4-Hydroxybenzenesulfonyl chloride

A solution of 7 g (30 mmol) of the sodium salt of4-hydroxybenzenesulfonic acid dihydrate in 40 ml of dimethylformamide isadded dropwise to a solution of 15.5 ml (181 mmol) of oxalyl chloride in120 ml of dichloromethane cooled to -30° C. The reaction medium isslowly brought back to ambient temperature and then stirred at ambienttemperature for 18 h. After the addition of 200 ml of ice, the reactionmedium is extracted with ethyl acetate. The organic phase is washed withwater and with a saturated aqueous solution of sodium chloride, driedover magnesium sulfate, filtered and concentrated. 6.2 g (100%) of4-hydroxybenzenesulfonyl chloride are obtained in the form of acolorless oil.

27.2: Methyl(S)-2-(4-benzylpiperazin-1-yl)-3-(4-hydroxybenzenesulfonylamino)propanoate

In a manner analogous to example 3.6, using 5.8 g (30 mmol) of4-hydroxybenzenesulfonyl chloride and 7.7 g (20 mmol) of methyl(S)-3-amino-2-(4-benzylpiperazin-1-yl)propanoate trihydrochloride(prepared as described in example 17.5), 2.25 g (27%) of methyl(S)-2-(4-benzylpiperazin-1-yl)-3-(4-hydroxybenzenesulfonylamino)propanoateare obtained in the form of a white solid.

27.3: Methyl(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoate

In a manner analogous to example 11.1, using 500 mg (1.1 mmol) of methyl(S)-2-(4-benzylpiperazin-1-yl)-3-(4-hydroxybenzenesulfonylamino)propanoateand 370 mg (1.7 mmol) of(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-yl)methanol (prepared asdescribed in example 25.2), 350 mg (50%) of methyl(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoateare obtained in the form of a colorless oil.

27.4:(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmeth-oxy)benzenesulfonylamino]propanoicacid

In a manner analogous to example 3.7, using 350 mg (0.5 mmol) of methyl(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoate,165 mg (48%) of(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoicacid are obtained in the form of a white solid.

27.5:(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide

In a manner analogous to example 3.8, using 165 mg (0.3 mmol) of(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoicacid, 50 mg (29%) of(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-trifluoromethylpyrazolo[1,5-α]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamideare obtained in the form of a white solid with a melting point of 138°C.

¹H NMR (δ, DMSO): 2.20 (m, 4H); 2.38 (m, 4H); 2.65-2.75 (m, 1H);2.86-2.98 (m, 2H); 3.35 (m, 2H); 5.37 (s, 2H); 7.10-7.25 (m, 8H);7.35-7.44 (m, 2H); 7.68 (d, J=8.9 Hz, 2H); 7.98 (d, J=9 Hz, 1H); 8.81(m, 2H); 10.52 (s, 1H).

EXAMPLE 28 Enzymatic assay for TACE Inhibition

Description of the Assay

The products are solubilized in DMSO at a concentration of 10 mM. Aserial 3-fold dilution over 10 points is carried out so as to have aconcentration range of from 10 μM to 0.5 nM final concentration.

The TACE enzyme is an internal production (carried out according to thepublication “protein Eng Des Sel 2006, 19,155-161”) and is added so asto have a signal equivalent to 6 times the background noise in 2 h at37° C. The reaction is carried out in 50 mM Tris buffered mediumcontaining 4% glycerol, pH 7.4. The fluorescent substrate isMCA-Pro-Leu-Ala-Val-(Dpa)-Arg-Ser-Ser-Arg-NH₂ (R&D systems, reference:ES003). The substrate is cleaved by the enzyme between the alanine andthe valine, thus releasing a fluorescent peptide (excitation: 320 nm,emission: 420 nm). The substrate is used at 40 μM. The reaction iscarried out in a final volume of 10 μl (4 μl inhibitor, 4 μl substrate,2 μl enzyme) in a low volume 384-well plate (Corning reference: 3676).The plate is incubated at ambient temperature for 2 h, and then read byfluorescence on a Pherastar reader (BMG labtech). The 10₅₀ is determinedusing mathematical processing software (XLfit).

Product Assay

Example % TACE inhibition at IC50 - No. 10 μM TACE (nM) ex1 100 87 ex2100 32 ex4 95 497 ex5 99 21 ex6 99 52 ex8 100 127 ex9 100 147 ex10 93 47ex11 93 24 ex13 96 108 ex14 98 64 ex16 96 168 ex17 91 62 ex18 90 67 ex1992 41 ex21 97 63 ex23 97 53 ex24 98 86 ex26 98 33

On the basis of the results obtained in the TACE enzymatic assaydescribed above, the compounds claimed in the present invention areTNF-alpha converting enzyme (TACE) inhibitors and consequently may bepotential active ingredients for the treatment of pathologicalconditions for which reducing TNF-alpha production would be of greatinterest.

Example 29 Selectivity Assay

Principle of the Assay:

The molecules are dose-response tested on the following enzymes: MMP1,MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as thatdescribed for the TACE enzyme in example 28, but with differentsubstrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems,reference: ES003).

The enzymes are purchased from Calbiochem.

Product Assay:

IC50 (nM) Example MMP1 MMP3 MMP9 ADAM9 ADAM10 TACE 5 51003200 >10000 >10000 >10000 21 18 670 849 >10000 9254 >10000 67 19 23031770 >10000 3054 >10000 41 20 3935 4775 >10000 >10000 >10000 140 21 1166887 >10000 >10000 >10000 63 23 2221 1065 >10000 >10000 >10000 53 24 20591878 >10000 >10000 >10000 86 26 969 574 >10000 >10000 >10000 16Apratastat 145 10 82 85 71 5

On the basis of the results obtained in the selectivity assay describedabove, these compounds are also very selective for TACE compared withthe other ADAMs and MMPs, i.e. they have IC₅₀ values for other ADAMs orMMPs that are at least 10 times higher than that obtained for TACE, andmore advantageously at least 100 times higher. As it happens, insofar asit is known that the nonselective inhibition of these families ofenzymes induces adverse side effects observed in vivo, the selectiveinhibition of TACE compared with these other enzymes should make itpossible to reduce adverse side effects when these molecules areadministered for the treatment of pathological conditions for whichreducing TNF-alpha production would be of great interest.

1. A compound of formula (I), a salt thereof, or an enantiomer thereof,

in which: R₁ represents a hydrogen, an alkyl radical, a substitutedalkyl radical, an alkenyl radical, a substituted alkenyl radical, analkynyl radical, a substituted alkynyl radical, an aralkyl radical, asubstituted aralkyl radical, a heteroaralkyl radical, a substitutedheteroaralkyl radical, a —C(O)—R₄ radical, a —SO₂—R₄ radical, or aC(O)OR₄ radical, with R₄ having the meanings given hereinafter; R₂ is ahydrogen atom or a lower alkyl radical; R₃ is an alkyl radical, asubstituted alkyl radical, an alkenyl radical, a substituted alkenylradical, an alkynyl radical, a substituted alkynyl radical, an arylradical, a substituted aryl radical, an aralkyl radical, a substitutedaralkyl radical, a heterocyclic radical, a substituted heterocyclicradical, a cycloalkyl radical, a substituted cycloalkyl radical, aheteroaryl radical, a substituted heteroaryl radical, a heteroaralkylradical, or a substituted heteroaralkyl radical; R₄ is an alkyl radical,a substituted alkyl radical, an alkenyl radical, a substituted alkenylradical, an alkynyl radical, a substituted alkynyl radical, an arylradical, a substituted aryl radical, an aralkyl radical, or asubstituted aralkyl radical; and, n is 1.